Compounds and uses thereof

ABSTRACT

The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.

BACKGROUND

Disorders can be affected by the BAF complex. BRD9 is a component of theBAF complex. The present invention relates to useful compositions andmethods for the treatment of BAF complex-related disorders, such ascancer and infection.

SUMMARY

Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9gene on chromosome 5. BRD9 is a component of the BAF (BRG1- orBRM-associated factors) complex, a SWI/SNF ATPase chromatin remodelingcomplex, and belongs to family IV of the bromodomain-containingproteins. BRD9 is present in several SWI/SNF ATPase chromatin remodelingcomplexes and is upregulated in multiple cancer cell lines. Accordingly,agents that reduce the levels and/or activity of BRD9 may provide newmethods for the treatment of disease and disorders, such as cancer andinfection. The inventors have found that depleting BRD9 in cells resultsin the depletion of the SS18-SSX fusion protein in those cells. TheSS18-SSX fusion protein has been detected in more than 95% of synovialsarcoma tumors and is often the only cytogenetic abnormality in synovialsarcoma. Additionally, evidence suggests that the BAF complex isinvolved in cellular antiviral activities. Thus, agents that degradeBRD9 (e.g., compounds) are useful in the treatment of disorders (e.g.,cancers or infections) related to BAF, BRD9, and/or SS18-SSX.

The present disclosure features compounds and methods useful fortreating BAF-related disorders (e.g., cancer or infection).

In an aspect, the disclosure features a compound having the structure ofFormula I:

A-L-B  Formula I,

-   -   where    -   A is a BRD9 binding moiety;    -   B is a degradation moiety; and    -   L has the structure of Formula II:

A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)—(F³)_(o2)-(E²)_(p)-A²,  FormulaII

-   -   where    -   A¹ is a bond between the linker and A;    -   A² is a bond between B and the linker;    -   each of m, n, o1, o2, and p is, independently, 0 or 1;    -   each of E¹ and E² is, independently, O, S, NR^(N), optionally        substituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀        alkenylene, optionally substituted C₂₋₁₀ alkynylene, optionally        substituted C₂-C₁₀ polyethylene glycol, or optionally        substituted C₁₋₁₀ heteroalkylene;    -   E³ is optionally substituted C₁-C₆ alkylene, optionally        substituted C₁-C₆ heteroalkylene, O, S, or NR^(N);    -   each R^(N) is, independently, H, optionally substituted C₁₋₄        alkyl, optionally substituted C₂₋₄ alkenyl, optionally        substituted C₂₋₄ alkynyl, optionally substituted C₂₋₆        heterocyclyl, optionally substituted C₆₋₁₂ aryl, or optionally        substituted C₁₋₇ heteroalkyl;    -   C³ is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and    -   each of F¹, F², and F³ is, independently, optionally substituted        C₃-C₁₀ carbocyclylene, optionally substituted C₂₋₁₀        heterocyclylene, optionally substituted C₆-C₁₀ arylene, or        optionally substituted C₂-C₉ heteroarylene,    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, the linker has the structure of Formula IIa:

A¹-(E¹)-(F¹)—(C³)_(m)-(E²)_(p)-A².  Formula IIa

In some embodiments, the linker has the structure of Formula IIb:

A¹-(E¹)-(F¹)-(E²)_(p)-A².  Formula IIb

In some embodiments, the linker has the structure of Formula IIc:

A¹-(E¹)-(F¹)-A².  Formula IIc

In some embodiments, the linker has the structure of Formula IId:

A¹-(E¹)-(F¹)—(C³)_(m)—(F²)_(o1)-A².  Formula IId

In some embodiments, the linker has the structure of Formula IIe:

A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².  Formula IIe

In some embodiments, the linker has the structure of Formula IIf:

A¹-(E¹)-(F¹)—(C₃)_(m)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².  Formula IIf

In some embodiments, the linker has the structure of Formula IIg:

A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-A,  Formula IIg

In some embodiments, each of E¹ and E² is, independently, NR^(N),optionally substituted C₁₋₁₀ alkylene, optionally substituted C₂-C₁₀polyethylene glycolene, or optionally substituted C₁₋₁₀ heteroalkylene.

In some embodiments, E³ is optionally substituted C₁-C₆ alkylene, O, S,or NR^(N);

-   -   In some embodiments, E³ is optionally substituted C₁-C₆        alkylene. In some embodiments, E³ is optionally substituted        C₁-C₃ alkylene. In some embodiments, E³ is O, S, or NR^(N).

In some embodiments, E³ is C₁-C₆ alkylene. In some embodiments, E³ isC₁-C₃ alkylene. In some embodiments, E³ is O.

In some embodiments, E³ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E³ is

In some embodiments, each R^(N) is, independently, H or optionallysubstituted C₁₋₄ alkyl.

In some embodiments, each R^(N) is, independently, H or methyl.

In some embodiments, E¹ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E¹ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

-   -   where    -   b is 0, 1, 2, 3, 4, 5, or 6;    -   R^(a) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl;    -   R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl; and    -   R^(c) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, R^(a) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(b) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(c) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(a) is H or methyl. In some embodiments, R^(b) isH or methyl. In some embodiments, R^(c) is H or methyl.

In some embodiments, b is 0, 1, 2, or 3. In some embodiments, b is 0. Insome embodiments, b is 1. In some embodiments, b is 2. In someembodiments, b is 3.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E² is O, NR^(w),

-   -   wherein    -   c is 0, 1, 2, 3, 4, 5, 6, 7, or 8;    -   d is 0, 1, 2, or 3;    -   e is 0, 1, 2, 3, 4, 5, or 6;    -   f is 0, 1, 2, 3, or 4;    -   R^(d) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl;    -   R^(e) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl;    -   R^(f) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl;    -   R^(g) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl; and    -   W is O or NR^(w), wherein R^(w) is H or optionally substituted        C₁-C₆ alkyl.

In some embodiments, E² is O, NR^(w),

In some embodiments, R^(d) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(e) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(f) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(g) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(w) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(d) is H or methyl. In some embodiments, R^(e) isH or methyl. In some embodiments, R^(f) is H or methyl. In someembodiments, R^(g) is H or methyl. In some embodiments, R^(w) is H ormethyl.

In some embodiments, E² is

In some embodiments, E² is O,

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₃-C₁₀ carbocyclylene.

In some embodiments, the C₃-C₁₀ carbocyclylene is monocyclic. In someembodiments, the C₃-C₁₀ carbocyclylene is polycyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is bicyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is bridged. In someembodiments, the C₃-C₁₀ carbocyclylene is fused. In some embodiments,the C₃-C₁₀ carbocyclylene is spirocyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is

In some embodiments, F² is

In some embodiments, the C₃₋₁₀ carbocyclylene is

In some embodiments, F¹ is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₂-C₉ heterocyclylene.

In some embodiments, the C₂-C₉ heterocyclylene is monocyclic. In someembodiments, the C₂-C₉ heterocyclylene is polycyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bicyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bridged. In someembodiments, the C₂-C₉ heterocyclylene is fused. In some embodiments,the C₂-C₉ heterocyclylene is spirocyclic.

In some embodiments, the C₂-C₉ heterocyclylene includes a quaternaryamine.

In some embodiments, the C₂-C₉ heterocyclylene is

-   -   where    -   q1 is 0, 1, 2, 3, or 4;    -   q2 is 0, 1, 2, 3, 4, 5, or 6;    -   q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8;    -   each R^(h) is, independently, ²H, halogen, optionally        substituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4); or two R^(h)        groups, together with the carbon atom to which each is attached,        combine to form optionally substituted C₃-C₁₀ carbocyclyl or        optionally substituted C₂-C₉ heterocyclyl; or two R^(h) groups,        together with the carbon atoms to which each is attached,        combine to form optionally substituted C₃-C₁₀ carbocyclyl or        optionally substituted C₂-C₉ heterocyclyl;    -   R^(i1) is H or optionally substituted C₁-C₆ alkyl;    -   R^(i2) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, or optionally substituted C₃-C₆        carbocyclyl;    -   R^(i3) is H or optionally substituted C₁-C₆ alkyl; and    -   R^(i4) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, each R^(h) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In some embodiments,R^(i1) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i2) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i3) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i4) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, each R^(h) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In some embodiments,each R^(h) is, independently, halogen, optionally substituted C₁-C₆alkyl, or NR^(i3)R^(i4).

In some embodiments, each R^(h) is, independently, ²H, halogen, cyano,optionally substituted C₁-C₆alkyl, OR^(i2), or NR^(i3)R^(i4). In someembodiments, two R^(h) groups, together with the carbon atom to whicheach is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl. In someembodiments, two R^(h) groups, together with the carbon atoms to whicheach is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each R^(h) is, independently, ²H, F, methyl,

In some embodiments, each R^(h) is, independently, F, methyl, orNR^(i3)R^(i4).

In some embodiments, q1 is 0, 1, or 2. In some embodiments, q1 is 0. Insome embodiments, q1 is 1. In some embodiments, q1 is 2.

In some embodiments, q2 is 0, 1, or 2. In some embodiments, q2 is 0. Insome embodiments, q2 is 1. In some embodiments, q2 is 2.

In some embodiments, q3 is 0, 1, or 2. In some embodiments, q3 is 0. Insome embodiments, q3 is 1. In some embodiments, q3 is 2.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F³ is

In some embodiments, F³ is

In some embodiments, R^(i1) is H or methyl. In some embodiments, R^(i2)is H or methyl. In some embodiments, R^(i3) is H or methyl. In someembodiments, R^(i4) is H or methyl.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, the C₂-C₉ heterocyclyl is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F³ is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₆-C₁₀ arylene.

In some embodiments, the C₆-C₁₀ arylene is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₂-C₉ heteroarylene.

In some embodiments, the C₂-C₉ heteroarylene is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, C³ is

In some embodiments, C³ is

In some embodiments, m is 1. In some embodiments, p is 1.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of:

In some embodiments, the linker is absent.

In some embodiments, the linker is optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂₋₁₀ heterocyclylene, optionallysubstituted C₆₋₁₀ arylene, or optionally substituted C₂-C₉heteroarylene.

In some embodiments, the linker is optionally substituted C₃-C₁₀carbocyclylene or optionally substituted C₂₋₁₀ heterocyclylene. In someembodiments, the linker is optionally substituted C₆-C₁₀ arylene oroptionally substituted C₂-C₉ heteroarylene.

In some embodiments, the linker is optionally substituted C₂₋₁₀heterocyclylene.

In some embodiments, the C₂-C₉ heterocyclylene is monocyclic. In someembodiments, the C₂-C₉ heterocyclylene is polycyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bicyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bridged. In someembodiments, the C₂-C₉ heterocyclylene is fused. In some embodiments,the C₂-C₉ heterocyclylene is spirocyclic.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the degradation moiety is a ubiquitin ligasebinding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprisesCereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse doubleminute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, orderivatives or analogs thereof.

In some embodiments, the degradation moiety is a ubiquitin ligasebinding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprisesCereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse doubleminute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, orderivatives or analogs thereof.

In some embodiments, the degradation moiety includes the structure ofFormula Y:

-   -   where    -   A² is a bond between the degradation moiety and the linker;    -   v1 is 0, 1, 2, 3, 4, or 5;    -   u1 is 1, 2, or 3;    -   T¹ is a bond or

-   -   T² is

-   -   R^(5A) is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   each R^(J1) is, independently, halogen, optionally substituted        C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl;    -   J^(A) is absent, O, optionally substituted amino, optionally        substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆        heteroalkyl; and    -   J is absent, optionally substituted C₃-C₁₀ carbocyclylene,        optionally substituted C₆-C₁₀ arylene, optionally substituted        C₂-C₉ heterocyclylene, or optionally substituted C₂-C₉        heteroarylene, or a pharmaceutically acceptable salt thereof.

In some embodiments, T² is

In some embodiments, T² is or

In some embodiments, T² is

In some embodiments, T² is

In some embodiments, the structure of Formula Y has the structure ofFormula Y1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, T¹ is a bond. In some embodiments, T¹ is

In some embodiments, the structure of Formula Y has the structure ofFormula Y2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Y has the structure ofFormula Z:

or a pharmaceutically acceptable salt thereof.

In some embodiments, u1 is 1. In some embodiments, u1 is 2. In someembodiments u1 is 3.

In some embodiments, the structure of Formula Z has the structure ofFormula AA0:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Z has the structure ofFormula AB:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Z has the structure ofFormula AC:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J^(A) is absent. In some embodiments, J^(A) isoptionally substituted C₁-C₆ alkyl. In some embodiments, J^(A) isoptionally substituted C₁-C₆ heteroalkyl. In some embodiments, J^(A) isO or optionally substituted amino.

In some embodiments, J^(A) is

In some embodiments, the structure of Formula AA0 has the structure ofFormula AA0:

or a pharmaceutically acceptable salt thereof.

In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0.In some embodiments, v1 is 1. In some embodiments, v1 is 2. In someembodiments, v1 is 3.

In some embodiments, the structure of Formula AA has the structure ofFormula AA1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AB has the structure ofFormula AB1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AC has the structure ofFormula AC1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J is absent. In some embodiments, J is optionallysubstituted C₃-C₁₀ carbocyclylene or optionally substituted C₆-C₁₀arylene. In some embodiments, J is optionally substituted C₂-C₉heterocyclylene or optionally substituted C₂-C₉ heteroarylene.

In some embodiments, J is optionally substituted heterocyclylene. Insome embodiments, J is optionally substituted C₆-C₁₀ arylene.

In some embodiments, J is

In some embodiments, the structure of Formula AA has the structure ofFormula AA2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AA has the structure ofFormula AA3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AA has the structure ofFormula AA4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(A5) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(A5) is H or methyl. In some embodiments, R^(A5)is H. In some embodiments, R^(A5) is methyl. In some embodiments, R^(A5)is

In some embodiments, the structure of Formula AA has the structure ofFormula A:

-   -   where    -   Y1 is

-   -   R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   R^(A6) is H or optionally substituted C₁-C₆ alkyl; and R^(A7) is        H or optionally substituted C₁-C₆ alkyl; or R^(A6) and R^(A7),        together with the carbon atom to which each is bound, combine to        form optionally substituted C₃-C₆carbocyclyl or optionally        substituted C₂-C₅ heterocyclyl; or R^(A6) and R^(A7), together        with the carbon atom to which each is bound, combine to form        optionally substituted C₃-C₆carbocyclyl or optionally        substituted C₂-C₅ heterocyclyl;    -   R^(A8) is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   each of R^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H,        A², halogen, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀        carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆        carbocyclyl, hydroxyl, thiol, or optionally substituted amino;        or R^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and        R^(A4), together with the carbon atoms to which each is        attached, combine to form        ; and        is optionally substituted C₆-C₁₀ aryl, optionally substituted        C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or        C₂-C₉ heterocyclyl, any of which is optionally substituted with        A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or        is substituted with A², or a pharmaceutically acceptable salt        thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3) and R^(A4) is,independently, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3) and R^(A4) is, H,A², halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, optionally substituted amino; or R^(A1) and R^(A2), R^(A2) andR^(A3), or R^(A3) and R^(A4), together with the carbon atoms to whicheach is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, each of R^(A1), R^(A2), R^(A3) and R^(A4) is,independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, R^(A1) is A². In some embodiments, R^(A2) is A². Insome embodiments, R^(A3) is A². In some embodiments, R^(A4) is A². Insome embodiments, R^(A5) is A².

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(A5) is H or

In some embodiments, R^(A5) is H. In some embodiments, R^(A5) is

In some embodiments, Y¹ is or

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, each of R^(A6) and R^(A7) is, independently, H, F,

or R^(A6) and R^(A7), together with the carbon atom to which each isbound, combine to form

In some embodiments, R^(A6) is H and R^(A7) is H.

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, the structure of Formula A has the structure ofFormula A1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A5:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A6:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A7:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A8:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A9:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A10:

or a pharmaceutically acceptable salt thereof.

In some embodiments, wherein the structure of Formula A is

or derivative or analog thereof.

In some embodiments, the structure of Formula A is

In some embodiments, the structure of Formula A is

or derivative or analog thereof.

In some embodiments,

is

where R^(A9) is H, A², optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl.

In some embodiments, the structure of Formula A is

In some embodiments, R^(A9) is H, A², or optionally substituted C₁-C₆alkyl. In some embodiments, R^(A9) is H, A², or methyl. In someembodiments, R^(9A) is H. In some embodiments, R^(9A) is methyl. In someembodiments, R^(A9) is A².

In some embodiments, the structure of Formula A is

In some embodiments, the structure of Formula AA has the structure ofFormula B:

-   -   where    -   R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   each of R^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H,        A², halogen, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀        carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆        carbocyclyl, hydroxyl, thiol, or optionally substituted amino;        or R^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and        R^(A4), together with the carbon atoms to which each is        attached, combine to form        ; and        is optionally substituted C₆-C₁₀ aryl, optionally substituted        C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or        C₂-C₉ heterocyclyl, any of which is optionally substituted with        A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or        is substituted with A², or a pharmaceutically acceptable salt        thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is, H,A², halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, optionally substituted amino; or R^(A1) and R^(A2), R^(A2) andR^(A3), or R^(A3) and R^(A4), together with the carbon atoms to whicheach is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, each of R^(A1), R^(A2), R^(A3) and R^(A4) is,independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, R^(A1) is A². In some embodiments, R^(A2) is A². Insome embodiments, R^(A3) is A². In some embodiments, R^(A4) is A². Insome embodiments, R^(A5) is A².

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(A5) is H or

In some embodiments, R^(A5) is H. In some embodiments, R^(A5) is

In some embodiments, the structure of Formula B has the structure ofFormula B1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B is

In some embodiments, the structure of Formula B is

In some embodiments, the structure of Formula B is

In some embodiments, the ubiquitin ligase binding moiety comprises a vonHippel-Lindau ligand.

In some embodiments, the von Hippel-Lindau ligand has the structure of

or derivative or analog thereof.

In some embodiments, the degradation moiety includes the structure ofFormula C:

-   -   where    -   R^(B1) is H, A², optionally substituted C₁-C₆ alkyl, or        optionally substituted C₁-C₆ heteroalkyl;    -   R^(B2) is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   R^(B3) is A², optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀        carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally        substituted C₁-C₆ alkyl C₆₋₁₀ aryl;    -   R^(B4) is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or        optionally substituted C₁-C₆alkyl C₆-C₁₀ aryl;    -   R^(B5) is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   v2 is 0, 1, 2, 3, or 4;    -   each R^(B6) is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino;        and    -   each of R^(B7) and R^(B8) is, independently, H, halogen,        optionally substituted C₁-C₆ alkyl, or optionally substituted        C₆-C₁₀ aryl,    -   where one of R^(B1) and R^(B3) is A², or a pharmaceutically        acceptable salt thereof.

In some embodiments, the structure of Formula C is

or derivative or analog thereof.

In some embodiments, the structure of Formula C is

In some embodiments, the degrader moiety includes the structure ofFormula D:

-   -   where    -   A² is a bond between B and the linker;    -   each of R^(C1), R^(C2), and R^(C7) is, independently, H,        optionally substituted C₁-C₆ alkyl, or optionally substituted        C₁-C₆ heteroalkyl;    -   R^(C3) is optionally substituted C₁-C₆ alkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or        optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;    -   R^(C5) is optionally substituted C₁-C₆ alkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or        optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;    -   v3 is 0, 1, 2, 3, or 4;    -   each R^(C6) is, independently, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₆        heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxy,        thiol, or optionally substituted amino;    -   v4 is 0, 1, 2, 3, or 4; and    -   each R^(C9) is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino,        or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula D is

or derivative or analog thereof.

In some embodiments, the degrader moiety includes the structure ofFormula E:

-   -   where    -   A² is a bond between B and the linker;    -   each of R^(C10) and R^(C11) is, independently, H, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₁₀        carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally        substituted C₁-C₆ alkyl C₆-C₁₀ aryl;    -   v5 is 0, 1, 2, 3, or 4;    -   each R^(C12) is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino;    -   v6 is 0, 1, 2, 3, or 4; and    -   each R²¹ is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino,        or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula E is

or derivative or analog thereof.

In some embodiments, the degradation moiety includes the structure ofFormula FA:

-   -   where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

-   -   is a single bond or a double bond;    -   u2 is 0, 1, 2, or 3;    -   A² is a bond between the degrader and the linker;    -   Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   Y^(Fb) is NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))₂, O, or S;    -   Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   each of R^(Fb), R^(Fc), R^(Fd), and R^(Fe) is, independently, H,        alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl,        carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl₂;    -   or R^(Fb) and R^(Fc), together with the carbon atom to which        each is attached, combine to form a 3-, 4-, 5-, or 6-membered        spirocarbocyclylene, or a 4-, 5-, or 6-membered        spiroheterocyclylene comprising 1 or 2 heteroatoms selected from        N and O;    -   or R^(Fd) and R^(Fe), together with the carbon atom to which        each is attached, combine to form a 3-, 4-, 5-, or 6-membered        spirocarbocyclylene, or a 4-, 5-, or 6-membered        spiroheterocyclylene comprising 1 or 2 heteroatoms selected from        N and O; and    -   or R^(Fd) and R^(Fb), together with the carbon atoms to which        each is attached, combine to form a 1, 2, 3, or 4 carbon bridged        ring;    -   each of Y^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2),        C(R^(FF2))₂, C(O), N, NH, NR^(FF3), O, S, or S(O);    -   Y^(Fe) is a bond or a divalent moiety attached to Y^(Fd) and        Y^(Ff) that contains 1 to 5 contiguous carbon atoms that form a        3 to 8-membered ring,        -   wherein 1, 2, or 3 carbon atoms can be replaced with a            nitrogen, oxygen, or sulfur atom;        -   wherein one of the ring atoms is substituted with A² and the            others are substituted with one or more groups independently            selected from H and R^(FF1); and        -   wherein the contiguous atoms of Y^(Fe) can be attached            through a single or double bond;    -   each R^(FF1) is, independently, H, alkyl, alkenyl, alkynyl,        aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl,        amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl,        alkylamino, alkylhydroxyl, or haloalkyl;    -   each R^(FF2) is, independently, alkyl, alkene, alkyne, halogen,        hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH,        —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including        alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including        alkyl)(aliphatic including alkyl), —NHSO₂alkyl,        —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl,        —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,        aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic,        carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl;        and    -   R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl,        or —C(O)Oalkyl,    -   wherein if Y^(Fd) or Y^(Ff) is substituted with A², then Y^(Fe)        is a bond, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula FA has the structure ofFormula FA1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety includes the structure ofFormula FB:

-   -   where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

-   -   A² is a bond between the degrader and the linker;    -   Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   each of Y^(Fb) and Y^(Fg) is, independently, NH, NR^(FF1), CH₂,        CHR^(FF1), C(R^(FF1))₂, O, or S;    -   Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   each of R^(Fb), R^(Fc), R^(Fd), R^(Fe), R^(Ff), and R^(Fg) is,        independently, H, alkyl, aliphatic, heteroaliphatic, aryl,        heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or        —Nalkyl₂;    -   or R^(Fb) and R^(Fc), together with the carbon atom to which        each is attached, combine to form a 3-, 4-, 5-, or 6-membered        spirocarbocyclylene, or a 4-, 5-, or 6-membered        spiroheterocyclylene comprising 1 or 2 heteroatoms selected from        N and O;    -   or R^(Fd) and R^(Fe), together with the carbon atom to which        each is attached, combine to form a 3-, 4-, 5-, or 6-membered        spirocarbocyclylene, or a 4-, 5-, or 6-membered        spiroheterocyclylene comprising 1 or 2 heteroatoms selected from        N and O;    -   or R^(Ff) and R^(Fg), together with the carbon atom to which        each is attached, combine to form a 3-, 4-, 5-, or 6-membered        spirocarbocyclylene, or a 4-, 5-, or 6-membered        spiroheterocyclylene comprising 1 or 2 heteroatoms selected from        N and O;    -   or R^(Fd) and R^(Fb), together with the carbon atoms to which        each is attached, combine to form a 1, 2, 3, or 4 carbon bridged        ring;    -   or R^(Fd) and R^(Ff), together with the carbon atoms to which        each is attached, combine to form a 1, 2, 3, or 4 carbon bridged        ring;    -   or R^(Fb) and R^(Fg), together with the carbon atoms to which        each is attached, combine to form a 1, 2, 3, or 4 carbon bridged        ring;    -   each of Y^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2),        C(R^(FF2))₂, C(O), N, NH, NR^(FF3), O, S, or S(O);    -   Y^(Fe) is a bond or a divalent moiety attached to Y^(Fd) and        Y^(Ff) that contains 1 to 5 contiguous carbon atoms that form a        3 to 8-membered ring,        -   wherein 1, 2, or 3 carbon atoms can be replaced with a            nitrogen, oxygen, or sulfur atom;        -   wherein one of the ring atoms is substituted with A² and the            others are substituted with one or more groups independently            selected from H and R^(FF1); and        -   wherein the contiguous atoms of Y^(Fe) can be attached            through a single or double bond;    -   each R^(FF1) is, independently, H, alkyl, alkenyl, alkynyl,        aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl,        amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl,        alkylamino, alkylhydroxyl, or haloalkyl;    -   each R^(FF2) is, independently, alkyl, alkene, alkyne, halogen,        hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH,        —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including        alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including        alkyl)(aliphatic including alkyl), —NHSO₂alkyl,        —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl,        —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,        aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic,        carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl;        and    -   R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl,        or —C(O)Oalkyl,    -   wherein if Y^(Fd) or Y^(Ff) is substituted with A², then Y^(Fe)        is a bond, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula FB has the structure ofFormula FB1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety includes the structure ofFormula F1:

where A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(F1) is absent. In some embodiments, R^(F1) is O.

In some embodiments, the structure of Formula F1 is

In some embodiments, the degradation moiety includes the structureFormula F2:

where A² is a bond between the degrader and the linker; and Y² is CH₂ orNH, or a pharmaceutically acceptable salt thereof.

In some embodiments, Y² is NH. In some embodiments, Y² is CH₂.

In some embodiments, structure of Formula F2 is

In some embodiments, the degradation moiety includes the structureFormula G:

where A² is a bond between the degrader and the linker; and Y³ is CH₂ orNH, or a pharmaceutically acceptable salt thereof.

In some embodiments, Y³ is NH. In some embodiments, Y³ is CH₂.

In some embodiments, structure of Formula G is

The degradation moiety may also include structures found in, e.g.,WO2017/197036; WO2019/204354, WO2019/236483, WO2020/010177; andWO2020/010227, the structures of which are herein incorporated byreference.

In some embodiments, A hast the structure of Formula III:

-   -   where    -   R⁴ is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₁-C₆        heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl; Z¹ is        N or CR⁵;    -   Z² is N or CR^(6a);    -   Z³ is N or CR^(6b);    -   R⁵ is H, halogen, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀        carbocyclyl, or optionally substituted C₆-C₁₀ aryl;    -   R^(6a) is H, halogen, cyano, optionally substituted C₁-C₆alkyl,        optionally substituted C₁-C₆ heteroalkyl, optionally substituted        C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally        substituted amino; R^(6b) is H, halogen, cyano, optionally        substituted C₁-C₆ alkyl, optionally substituted C₁-C₆        heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl,        optionally substituted C₂-C₉ heterocyclyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally        substituted amino; or R^(6a) and R^(6b), together with the        carbon atoms to which each is attached, combine to form        optionally substituted C₆-C₁₀ aryl or optionally substituted        C₂-C₉ heteroaryl;    -   s is 0, 1, 2, 3, or 4;    -   each R⁹ is, independently, halogen, optionally substituted C₁-C₆        alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉        heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxy,        thiol, or optionally substituted amino; and    -   A¹ is a bond between A and the linker, or a pharmaceutically        acceptable salt thereof.

In some embodiments, Z¹ is N. In some embodiments, Z¹ is CR⁵.

In some embodiments, Z² is N. In some embodiments, Z² is CR^(6a).

In some embodiments, Z³ is N. In some embodiments, Z³ is CR^(6b).

In some embodiments, Z¹ is CR⁵, Z² is CR^(6a), and Z³ is CR^(6b). Insome embodiments, Z¹ is N, Z² is CR^(6a), and Z² is CR^(6b). In someembodiments, Z¹ is CR⁵, Z² is N, and Z³ is CR^(6b). In some embodiments,Z¹ is N, Z² is CR^(6a), and Z³ is N. In some embodiments, Z¹ is N, Z² isN, and Z³ is CR^(6b). In some embodiments, Z¹ is CR⁵, Z² is N, and Z³ isN.

In some embodiments, R⁴ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R⁴ is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R⁴ is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R⁴ is H,

In some embodiments, R⁴ is

In some embodiments, R⁴ is H,

In some embodiments, R⁴ is H,

In some embodiments, R⁴ is H,

In some embodiments, R⁴ is H or

In some embodiments, R⁴ is H. In some embodiments, R⁴ is

In some embodiments, R⁵ is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₆-C₁₀ aryl. In some embodiments, R⁵ is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl. In someembodiments, R⁵ is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R⁵ is H,

In some embodiments, R⁵ is H,

In some embodiments, R⁵ is H or

In some embodiments, R⁵ is H. In some embodiments, R⁵ is

In some embodiments, R^(6a) is H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

In some embodiments, R^(6a) is H, halogen, cyano, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(6a) is H,halogen, cyano, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, R^(6a) is H,halogen, cyano, or optionally substituted C₁-C₆ alkyl. In someembodiments, R^(6a) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(6a) is H, F, cyano,

In some embodiments, R^(6a) is H, F, cyano,

In some embodiments, R^(6a) is H, F, cyano, or

In some embodiments, R^(6a) is

In some embodiments, R^(6a) is H or

In some embodiments, R^(6a) is H. In some embodiments, R^(6a) is

In some embodiments, R^(6b) is H, halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionallysubstituted amino.

In some embodiments, R^(6b) is H, halogen, cyano, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(6b) is H,halogen, cyano, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, R^(6b) is H,halogen, cyano, or optionally substituted C₁-C₆ alkyl. In someembodiments, Rob is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(6b) is H, F, cyano,

In some embodiments, R^(6b) is H, F, cyano,

In some embodiments, R^(6b) is H, F, cyano, or

In some embodiments, R^(6b) is

In some embodiment, R^(6b) is H or

In some embodiments, R^(6b) is H. In some embodiments, R^(6b) is

In some embodiments, R^(6a) and R^(6b), together with the carbon atomsto which each is attached, combine to form optionally substituted C₆-C₁₀aryl or optionally substituted C₂-C₉ heteroaryl.

In some embodiments, s is 0, 1, or 2. In some embodiment, s is 1 or 2.In some embodiments, s is 2.

In some embodiments, each R⁹ is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl. Insome embodiments, each R⁹ is, independently, optionally substitutedC₁-C₆ alkyl or optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R⁹ is

In some embodiments, each R⁹ is, independently, halogen,

In some embodiments, each R⁹ is, indecently, F, Cl,

In some embodiments, the structure of Formula III has the structure ofFormula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIId:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIe:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIg:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIh:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IIIi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula III has the structure ofFormula IV:

-   -   where    -   R⁷ is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₁-C₆        heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl;    -   R⁸ is H, halogen, optionally substituted C₁-C₆ alkyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀        carbocyclyl, or optionally substituted C₆-C₁₀ aryl;    -   s is 0, 1, 2, 3, or 4;    -   each R⁹ is, independently, halogen, optionally substituted C₁-C₆        alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉        heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxy,        thiol, or optionally substituted amino;    -   X¹ is N or CR^(10a);    -   X² is N or CR^(10b);    -   X³ is N or CR^(10c);    -   X⁴ is N or CR^(10d);    -   each of R^(10a), R^(10b), R^(10c), and R^(10d) is,        independently, H, halogen, hydroxy, optionally substituted C₁-C₆        alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉        heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxy,        thiol, or optionally substituted amino; and    -   A¹ is a bond between A and the linker, or a pharmaceutically        acceptable salt thereof.

In some embodiments, X¹ is N. In some embodiments, X¹ is CR^(10a). Insome embodiments, X² is N. In some embodiments, X² is CR^(10b). In someembodiments, X³ is N. In some embodiments, X³ is CR^(10c). In someembodiments, X⁴ is N. In some embodiments, X¹ is CR^(10d).

In some embodiments, X¹ is CR^(10a), X² is CR^(10b), X³ is CR^(10c), andX⁴ is CR^(10d). In some embodiments, X¹ is N, X² is CR^(10b), X³ isCR^(10c), and X⁴ is CR^(10d). In some embodiments, X¹ is CR^(10a), X² isN, X³ is CR^(10c), and X⁴ is CR^(10d). In some embodiments, X¹ isCR^(10a), X² is CR^(10b), X³ is N, and X⁴ is CR^(10d). In someembodiments, X¹ is CR^(10a), X² is CR^(10b), X³ is CR^(10c), and X⁴ isN. In some embodiments, X¹ is N, X² is N, X³ is CR^(10c), and X⁴ isCR^(10d). In some embodiments, X¹ is N, X² is CR^(10b), X³ is N, and X⁴is CR^(10d). In some embodiments, X¹ is N, X² is CR^(10b), X³ isCR^(10c), and X⁴ is N. In some embodiments, X¹ is CR^(10a), X² is N, X³is N, and X⁴ is CR^(10d). In some embodiments, X¹ is CR^(10a), X² is N,X³ is CR^(10c), and X⁴ is N. In some embodiments, X¹ is CR^(10a), X² isCR^(10b), X³ is N, and X⁴ is N.

In some embodiments, R⁷ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R⁷ is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, or optionallysubstituted C₃-C₁₀ carbocyclyl.

In some embodiments, R⁷ is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R⁷ is H,

In some embodiments, R⁷ is

In some embodiments, R⁷ is H,

In some embodiments, R⁷ is H,

In some embodiments, R⁷ is H,

In some embodiments, R⁷ is H or

In some embodiments, R⁷ is H. In some embodiment, R⁷ is

In some embodiments, R⁸ is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₆-C₁₀ aryl. In some embodiments, R⁸ is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl. In someembodiments, R⁸ is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R⁸ is H oroptionally substituted C₁-C₆ alkyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R⁸ is H,

In some embodiments, R⁸ is H,

In some embodiments, R⁸ is H or

In some embodiments, R⁸ is H. In some embodiments, R⁸ is

In some embodiments, s is 0, 1, or 2. In some embodiments, s is 1 or 2.In some embodiments, s is 2. In some embodiments, s is 1.

In some embodiments, each R⁹ is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl. Insome embodiments, each R⁹ is, independently, optionally substitutedC₁-C₆ alkyl or optionally substituted 1-C₆ heteroalkyl.

In some embodiments, R⁹ is

In some embodiments, each R⁹ is, independently, halogen,

In some embodiments, each R⁹ is, independently, F, Cl,

In some embodiments, R^(10a) is H, halogen, cyano, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(10a)is H, halogen, cyano, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, R^(10a) is H,halogen, cyano, or optionally substituted C₁-C₆ alkyl. In someembodiments, R^(10a) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(10a) is H, F, cyano,

In some embodiments, R^(10a) is H, F, cyano,

In some embodiments, R^(10a) is H, F, cyano, or

In some embodiments, R^(10a) is

In some embodiments, R^(10a) is H or

In some embodiments, R^(10a) is H. In some embodiments, R^(10a) is

In some embodiments, R^(10b) is H, halogen, cyano, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(10b)is H, halogen, cyano, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, R^(10b) is H,halogen, cyano, or optionally substituted C₁-C₆ alkyl. In someembodiments, R^(10b) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(10b) is H, F, cyano,

In some embodiments, R^(10b) is H, F, cyano, or

In some embodiments, R^(10b) is

In some embodiments, R^(10b) is H or

In some embodiments, R^(10b) is H. In some embodiments, R^(10b) is

In some embodiments, R^(10c) is H, halogen, cyano, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(10c)is H, halogen, cyano, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, R^(10c) is H,halogen, cyano, or optionally substituted C₁-C₆ alkyl. In someembodiments, R^(10c) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(10c) is H, F, cyano,

In some embodiments, R^(10c) is H, F, cyano,

In some embodiments, R^(10c) is H, F, cyano, or

In some embodiments, R^(10c) is

In some embodiments, R^(10c) is H or

In some embodiments, R^(10c) is H. In some embodiments, R^(10c) is

In some embodiments, R^(10d) is H, halogen, cyano, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl. In some embodiments, R^(10d)is H, halogen, cyano, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, R^(10d) is H,halogen, cyano, or optionally substituted C₁-C₆ alkyl. In someembodiments, R^(10d) is optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, R^(10d) is H, F, cyano,

In some embodiments, R^(10d) is H, F, cyano,

In some embodiments, R^(10d) is H, f, cyano, or

In some embodiments, R^(10d) is

In some embodiments, R^(10d) is H or

In some embodiments, R^(10d) is H. In some embodiments, R^(10d) is

In some embodiments, each of R^(10a), R^(10b), R^(10c), and R^(10d) is,independently, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, or optionally substituted amino.

In some embodiments, each of R^(10a), R^(10b), R^(10c), and R^(10d) is,independently, —NH₂,

In some embodiments, A includes the structure of Formula IVa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVd:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVe:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVg:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVh:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVj:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVk:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVm:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula IVn:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of any one of

In some embodiments, A includes the structure of Formula V

-   -   where    -   each R¹¹ and R¹⁶ is, independently, H, optionally substituted        C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl;    -   t is 0, 1, 2, 3, or 4;    -   each R¹² is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₆ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino;    -   u is 0, 1, 2, 3, or 4;    -   each R¹³ is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₆ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino;    -   each R¹⁴ and R¹⁵ is, independently, selected form the group        consisting of H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   G is optionally substituted C₁-C₆ alkylene, optionally        substituted C₆-C₁₀ arylene, or optionally substituted C₃-C₆        carbocyclylene; and    -   A¹ is a bond between A and the linker, or a pharmaceutically        acceptable salt thereof.

In some embodiments, A includes the structure of Formula VI:

-   -   where    -   Y² is CR¹⁷ or N;    -   R¹⁸ is A¹, optionally substituted C₆-C₁₀ aryl or C₂-C₉        heteroaryl;    -   R¹⁹ is H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   R²⁰ is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₆-C₁₀ aryl;    -   each R¹⁷, R²¹, and R²² is, independently, H, halogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₁-C₆        heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl,        optionally substituted C₂-C₉ heterocyclyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally        substituted amino;    -   R²³ is H or —NR²⁴R²⁵; and    -   each of R²⁴ and R²⁵ is, independently, H, A¹, optionally        substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆        heteroalkyl, or R²⁴ and R²⁵ combine to form optionally        substituted C₂-C₉ heterocyclyl,    -   where one of R¹⁸, R²⁴, or R²⁵ is A¹, or a pharmaceutically        acceptable salt thereof.

In some embodiments, A includes the structure of Formula VII:

-   -   where    -   each R^(26a), R^(26b), and R^(26c) is, independently, H, A¹,        halogen, optionally substituted C₁-C₆alkyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀        carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally        substituted amino;    -   each R^(27a) and R^(27b) is, independently, H, halogen,        optionally substituted C₁-C₆ alkyl, or optionally substituted        C₆-C₁₀ aryl;    -   R¹⁹ is H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   R²⁰ is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₆-C₁₀ aryl;    -   each R¹⁷, R²¹, and R²² is, independently, H, halogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₁-C₆        heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl,        optionally substituted C₂-C₉ heterocyclyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉        heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally        substituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally        substituted amino; and    -   each of R²⁴ and R²⁵ is, independently, H, A¹, optionally        substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆        heteroalkyl, or R²⁴ and R²⁵ combine to form optionally        substituted C₂-C₉ heterocyclyl,    -   where one of R^(26a), R^(26b), R^(26c), R²⁴, or R²⁵ is A¹, or a        pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of Formula VIII:

-   -   where    -   v is 0, 1, 2, 3, or 4;    -   each R²⁸ is, independently, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally        substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉        heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxy,        thiol, or optionally substituted amino;    -   R²⁹ is H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   R³¹ is H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   each R³⁰, R³², and R³³ is, independently, H, optionally        substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆        heteroalkyl; and    -   A¹ is a bond between A and the linker, or a pharmaceutically        acceptable salt thereof.

In some embodiments, A includes the structure of Formula IX:

-   -   where

-   -   Z⁴ is N or CR³⁸;    -   Z⁵ is N or CR³⁹;    -   R³⁴ is H, optionally substituted C₁-C₆ alkyl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₁-C₆        heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl;    -   R³⁵ is H, halogen, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ heteroalkyl, optionally substituted        C₃-C₆ carbocyclyl, or optionally substituted C₆-C₁₀ aryl;    -   R³⁷ is H, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ heteroalkyl;    -   R³⁸ is H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   R³⁹ is H, halogen, optionally substituted C₁-C₆ alkyl, or        optionally substituted C₆-C₁₀ aryl;    -   w is 0, 1, 2, 3, or 4;    -   each R³⁶ is, independently, halogen, optionally substituted        C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,        optionally substituted C₃-C₁₀ carbocyclyl, optionally        substituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₂-C₉ heteroaryl, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆        heteroalkenyl, hydroxy, thiol, or optionally substituted amino;        and    -   A¹ is a bond between A and the linker, or a pharmaceutically        acceptable salt thereof.

In some embodiments, Z⁴ is N. In some embodiments, Z⁴ is R³⁸. In someembodiments, Z⁵ is N. In some embodiments, Z⁵ is R³⁹.

In some embodiments, Z⁴ is N and Z⁵ is R³⁹. In some embodiments, Z⁴ isR³⁸ and Z⁵ is N. In some embodiments, Z⁴ is R³⁸ and Z⁵ is R³⁹.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, R³⁷ is H or optionally substituted C₁-C₆ alkyl. Insome embodiments, R³⁷ is H or

In some embodiments, R³⁸ is H or optionally substituted C₁-C₆ alkyl. Insome embodiments, R³⁸ is H or

In some embodiments, R³⁹ is H or optionally substituted C₁-C₆ alkyl. Insome embodiments, R³⁹ is H or

In some embodiments, R³⁴ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R³⁴ is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, oroptionally substituted C₃-C₁₀ carbocyclyl. In some embodiments, R³⁴ isH, optionally substituted C₁-C₆ alkyl, or optionally substituted C₃-C₁₀carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R³⁴ is H,

In some embodiments, R³⁴ is

In some embodiments, R³⁴ is H,

In some embodiments, R³⁴ is H,

In some embodiments, R³⁴ is H,

In some embodiments, R³⁴ is H or

In some embodiments, R³⁴ is H. In some embodiments, R³⁴ is

In some embodiments, R³⁵ is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₆-C₁₀ aryl. In some embodiments, R³⁵ is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl. In someembodiments, R³⁵ is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R³⁵ is H oroptionally substituted C₁-C₆ alkyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R³⁵ is H,

In some embodiments, R³⁵ is H,

In some embodiments, R³⁵ is H or

In some embodiments, R³⁵ is H. In some embodiments, R³⁵ is

In some embodiments, w is 0, 1, or 2. In some embodiments, w is 1 or 2.In some embodiments, w is 2.

In some embodiments, each R³⁶ is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl. Insome embodiments, each R³⁶ is, independently, optionally substitutedC₁-C₆ alkyl or optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, each R³⁶ is, independently,

In some embodiments, each R³⁶ is, independently, halogen,

In some embodiments, each R³⁶ is, independently, F, Cl,

In some embodiments, the structure of Formula IX has the structure ofFormula IXa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXd:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXe:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXg:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXh:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula IX has the structure ofFormula IXi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A includes the structure of:

where A¹ is a bond between A and the linker, or derivative or analogthereof.

In some embodiments, the compound has the structure of any one ofcompounds D1-D177 in Table 1A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D178-D371 in Table 1B, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound has the structure of anyone of compounds D372-D476 in Table 1D, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the compound has the structure of any one ofcompounds D1, D3, D6, D9-D20, D23, D33, D33-D35, D37-D40, D42, D44-D47,D50-D53, D56-D60, D67, D69, D71-D73, D75, D76, D80, D81, D89, D92, D100,D108, D113, D122-D124, D128-D132, D143, D152, D157, D167, D168, D170,D171, D173, and D176 in Table 1A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D178, D180, D184-D189, D191, D194, D197-D199, D201-D208,D211, D213-D230, D235-D244, D246, D247, D250-D263, D268, D269,D271-D275, D277, D279, D280, D287-D291, D297-D299, D300-D302, D304,D306-D308, D310, D312, D313, D315, D316, D318-D333, D335-D341,D343-D349, D353, D354, D356-D363, and D366-D371 in Table 1B, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound has the structure of any one of compounds D372-D379, D381,D382, D384-D388, D395-D428, D430, D431, D433, D434, D436, D438-D444,D448, D450, D453-D460, D462, D463, D465, D466, D471, and D476 in Table1D, or a pharmaceutically acceptable salt thereof.

In an aspect, the disclosure features a compound having the structure ofany one of compounds D1-D177 in Table 1A, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the disclosure features a compound having thestructure of any one of compounds D178-D371 in Table 1B, or apharmaceutically acceptable salt thereof.

In another aspect, the disclosure features a compound having thestructure of any one of compounds D372-D476 in Table 1D, or apharmaceutically acceptable salt thereof.

In another aspect, the disclosure features a compound having thestructure of any one of compounds DD1-DD10 in Table 1C, or apharmaceutically acceptable salt thereof.

In another aspect, the disclosure features a compound having thestructure of any one of compounds DD11-DD16 in Table 1E, or apharmaceutically acceptable salt thereof.

TABLE 1A Compounds D1-D177 of the Disclosure Com- pound No. Structure D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

D26

D27

D28

D29

D30

D31

D32

D33

D34

D35

D36

D37

D38

D39

D40

D41

D42

D43

D44

D45

D46

D47

D48

D49

D50

D51

D52

D53

D54

D55

D56

D57

D58

D59

D60

D61

D62

D63

D64

D65

D66

D67

D68

D69

D70

D71

D72

D73

D74

D75

D76

D77

D78

D79

D80

D81

D82

D83

D84

D85

D86

D87

D88

D89

D90

D91

D92

D93

D94

D95

D96

D97

D98

D99

D100

D101

D102

D103

D104

D105

D106

D107

D108

D109

D110

D111

D112

D113

D114

D115

D116

D117

D118

D119

D120

D121

D122

D123

D124

D125

D126

D127

D128

D129

D130

D131

D132

D133

D134

D135

D136

D137

D138

D139

D140

D141

D142

D143

D144

D145

D146

D147

D148

D149

D150

D151

D152

D153

D154

D155

D156

D157

D158

D159

D160

D161

D162

D163

D164

D165

D166

D167

D168

D169

D170

D171

D172

D173

D174

D175

D176

D177

TABLE 1B Compounds D178-D371 of the Disclosure Com- pound No. StructureD178

D179

D180

D181

D182

D183

D184

D185

D186

D187

D188

D189

D190

D191

D192

D193

D194

D195

D196

D197

D198

D199

D200

D201

D202

D203

D204

D205

D206

D207

D208

D209

D210

D211

D212

D213

D214

D215

D216

D217

D218

D219

D220

D221

D222

D223

D224

D225

D226

D227

D228

D229

D230

D231

D232

D233

D234

D235

D236

D237

D238

D239

D240

D241

D242

D243

D244

D245

D246

D247

D248

D249

D250

D251

D252

D253

D254

D255

D256

D257

D258

D259

D260

D261

D262

D263

D264

D265

D266

D267

D268

D269

D270

D271

D272

D273

D274

D275

D276

D277

D278

D279

D280

D281

D282

D283

D284

D285

D286

D287

D288

D289

D290

D291

D292

D293

D294

D295

D296

D297

D298

D299

D300

D301

D302

D303

D304

D305

D306

D307

D308

D309

D310

D311

D312

D313

D314

D315

D316

D317

D318

D319

D320

D321

D322

D323

D324

D325

D326

D327

D328

D329

D330

D331

D332

D333

D334

D335

D336

D337

D338

D339

D340

D341

D342

D343

D344

D345

D346

D347

D348

D349

D350

D351

D352

D353

D354

D355

D356

D357

D358

D359

D360

D361

D362

D363

D364

D365

D366

D367

D368

D369

D370

D371

TABLE 1C Compounds DD1-DD10 of the Disclosure Com- pound No. StructureDD1

DD2

DD3

DD4

DD5

DD6

DD7

DD8

DD9

DD10

TABLE 1D Compounds D372-D477 of the disclosure Compound No. StructureD372

D373

D374

D375

D376

D377

D378

D379

D380

D381

D382

D383

D384

D385

D386

D387

D388

D389

D390

D391

D392

D393

D394

D395

D396

D397

D398

D399

D400

D401

D402

D403

D404

D405

D406

D407

D408

D409

D410

D411

D412

D413

D414

D415

D416

D417

D418

D419

D420

D421

D422

D423

D424

D425

D426

D427

D428

D429

D430

D431

D432

D433

D434

D435

D436

D437

D438

D439

D440

D441

D442

D443

D444

D445

D446

D447

D448

D449

D450

D451

D452

D453

D454

D455

D456

D457

D458

D459

D460

D461

D462

D463

D464

D465

D466

D467

D468

D469

D470

D471

D472

D473

D474

indicates data missing or illegible when filed

TABLE 1E Compounds DD11-DD16 of the disclosure Compound No. StructureDD11

DD12

DD13

DD14

DD15

DD16

In another aspect, the disclosure features a pharmaceutical compositionincluding any of the foregoing compounds, or pharmaceutically acceptablesalts thereof, and a pharmaceutically acceptable excipient.

In an aspect, the disclosure features a method of inhibiting the leveland/or activity of BRD9 in a cell, the method involving contacting thecell with an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof.

In another aspect, the disclosure features a method of reducing thelevel and/or activity of BRD9 in a cell, the method involving contactingthe cell with an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof.

In some embodiments, the cell is a cancer cell.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In an aspect, the disclosure features a method of treating a BAFcomplex-related disorder in a subject in need thereof, the methodinvolving administering to the subject an effective amount of any of theforegoing compounds, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof. In some embodiments, the BAFcomplex-related disorder is cancer. In some embodiments, the BAFcomplex-related disorder is infection.

In another aspect, the disclosure features a method of treating anSS18-SSX fusion protein-related disorder in a subject in need thereof,the method involving administering to the subject an effective amount ofany of the foregoing compounds, or pharmaceutically acceptable saltsthereof, or a pharmaceutical composition thereof. In some embodiments,the SS18-SSX fusion protein-related disorder is cancer. In someembodiments, the SS18-SSX fusion protein-related disorder is infection.In some embodiments of any of the foregoing methods, the SS18-SSX fusionprotein is a SS18-SSX1 fusion protein, a SS18-SSX2 fusion protein, or aSS18-SSX4 fusion protein.

In yet another aspect, the disclosure features a method of treating aBRD9-related disorder in a subject in need thereof, the method involvingadministering to the subject an effective amount of any of the foregoingcompounds, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof. In some embodiments, theBRD9-related disorder is cancer. In some embodiments, the BRD9-relateddisorder is infection.

In some embodiments, the cancer is squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cellcarcinomas, cancer of the bladder, bowel, breast, cervix, colon,esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate,and stomach; leukemias; benign and malignant lymphomas, particularlyBurkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignantmelanomas; myeloproliferative diseases; sarcomas, including Ewing'ssarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In some embodiments, the infection is viral infection (e.g., aninfection with a virus of the Retroviridae family such as thelentiviruses (e.g. Human immunodeficiency virus (HIV) anddeltaretroviruses (e.g., human T cell leukemia virus I (HTLV-1), human Tcell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitisB virus (HBV)); Flaviviridae family (e.g. hepatitis C virus (HCV));Adenoviridae family (e.g. Human Adenovirus); Herpesviridae family (e.g.Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6),Herpesvitus K*, CMV, varicella-zoster virus); Papillomaviridae family(e.g. Human Papillomavirus (HPV, HPV E1)); Parvoviridae family (e.g.Parvovirus B19); Polyomaviridae family (e.g. JC virus and BK virus);Paramyxoviridae family (e.g. Measles virus); or Togaviridae family (e.g.Rubella virus)). In some embodiments, the disorder is Coffin Siris,Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or MultipleMeningioma. In an aspect, the disclosure features a method of treating acancer in a subject in need thereof, the method including administeringto the subject an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or any of the foregoingpharmaceutical compositions.

In some embodiments, the cancer is squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cellcarcinomas, cancer of the bladder, bowel, breast, cervix, colon,esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate,and stomach; leukemias; benign and malignant lymphomas, particularlyBurkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignantmelanomas; myeloproliferative diseases; sarcomas, including Ewing'ssarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In another aspect, the disclosure features a method for treating a viralinfection in a subject in need thereof. This method includesadministering to the subject an effective amount of any of the foregoingcompounds, or pharmaceutically acceptable salts thereof, or any of theforegoing pharmaceutical compositions. In some embodiments, the viralinfection is an infection with a virus of the Retroviridae family suchas the lentiviruses (e.g. Human immunodeficiency virus (HIV) anddeltaretroviruses (e.g., human T cell leukemia virus I (HTLV-1), human Tcell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitisB virus (HBV)), Flaviviridae family (e.g. hepatitis C virus (HCV)),Adenoviridae family (e.g. Human Adenovirus), Herpesviridae family (e.g.Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6),Herpesvitus K*, CMV, varicella-zoster virus), Papillomaviridae family(e.g. Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g.Parvovirus B19), Polyomaviridae family (e.g. JC virus and BK virus),Paramyxoviridae family (e.g. Measles virus), Togaviridae family (e.g.Rubella virus).

In another embodiment of any of the foregoing methods, the methodfurther includes administering to the subject an additional anticancertherapy (e.g., chemotherapeutic or cytotoxic agent or radiotherapy).

In particular embodiments, the additional anticancer therapy is: achemotherapeutic or cytotoxic agent (e.g., doxorubicin or ifosfamide), adifferentiation-inducing agent (e.g., retinoic acid, vitamin D,cytokines), a hormonal agent, an immunological agent, or ananti-angiogenic agent. Chemotherapeutic and cytotoxic agents include,but are not limited to, alkylating agents, cytotoxic antibiotics,antimetabolites, vinca alkaloids, etoposides, and others (e.g.,paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list ofadditional compounds having anticancer activity can be found in L.Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman's ThePharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGrawHill Companies, New York, NY.

In particular embodiments, the compound of the invention and theadditional anticancer therapy and any of the foregoing compounds orpharmaceutical compositions are administered within 28 days of eachother (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in anamount that together are effective to treat the subject.

Chemical Terms

The terminology employed herein is for the purpose of describingparticular embodiments and is not intended to be limiting.

For any of the following chemical definitions, a number following anatomic symbol indicates that total number of atoms of that element thatare present in a particular chemical moiety. As will be understood,other atoms, such as hydrogen atoms, or substituent groups, as describedherein, may be present, as necessary, to satisfy the valences of theatoms. For example, an unsubstituted C₂ alkyl group has the formula—CH₂CH₃. When used with the groups defined herein, a reference to thenumber of carbon atoms includes the divalent carbon in acetal and ketalgroups but does not include the carbonyl carbon in acyl, ester,carbonate, or carbamate groups. A reference to the number of oxygen,nitrogen, or sulfur atoms in a heteroaryl group only includes thoseatoms that form a part of a heterocyclic ring.

Herein a phrase of the form “optionally substituted X” (e.g., optionallysubstituted alkyl) is intended to be equivalent to “X, wherein X isoptionally substituted” (e.g., “alkyl, wherein said alkyl is optionallysubstituted”). It is not intended to mean that the feature “X” (e.g.,alkyl) per se is optional. As described herein, certain compounds ofinterest may contain one or more “optionally substituted” moieties. Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, means that one or more hydrogens of the designatedmoiety are replaced with a suitable substituent, e.g., any of thesubstituents or groups described herein. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby the present disclosure are preferably those that result in theformation of stable or chemically feasible compounds. The term “stable”,as used herein, refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production, detection,and, in certain embodiments, their recovery, purification, and use forone or more of the purposes disclosed herein.

The term “aliphatic,” as used herein, refers to a saturated orunsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” isintended herein to include, but is not limited to, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thusincorporates each of these definitions. In one embodiment, “aliphatic”is used to indicate those aliphatic groups having 1-20 carbon atoms. Thealiphatic chain can be, for example, mono-unsaturated, di-unsaturated,tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphaticgroups can be in a cis or trans configuration. In one embodiment, thealiphatic group contains from 1 to about 12 carbon atoms, more generallyfrom 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In oneembodiment, the aliphatic group contains from 1 to about 8 carbon atoms.In certain embodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅, or C₁-C₆. The specified ranges as used herein indicate analiphatic group having each member of the range described as anindependent species. For example, the term C₁-C₆ aliphatic as usedherein indicates a straight or branched alkyl, alkenyl, or alkynyl grouphaving from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to meanthat each of these is described as an independent species. For example,the term C₁-C₄ aliphatic as used herein indicates a straight or branchedalkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atomsand is intended to mean that each of these is described as anindependent species. In one embodiment, the aliphatic group issubstituted with one or more functional groups that results in theformation of a stable moiety.

The term “heteroaliphatic,” as used herein, refers to an aliphaticmoiety that contains at least one heteroatom in the chain, for example,an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate,nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.In one embodiment, the only heteroatom is nitrogen. In one embodiment,the only heteroatom is oxygen. In one embodiment, the only heteroatom issulfur. “Heteroaliphatic” is intended herein to include, but is notlimited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment,“heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. In one embodiment, the heteroaliphatic group is optionallysubstituted in a manner that results in the formation of a stablemoiety. Nonlimiting examples of heteroaliphatic moieties arepolyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide,polyglycolide, thioether, ether, alkyl-heterocycle-alkyl,—O-alkyl-O-alkyl, and alkyl-O-haloalkyl.

The term “acyl,” as used herein, represents a hydrogen or an alkyl groupthat is attached to a parent molecular group through a carbonyl group,as defined herein, and is exemplified by formyl (i.e., a carboxyaldehydegroup), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplaryunsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1to 21 carbons.

The term “alkyl,” as used herein, refers to a branched or straight-chainmonovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbonatoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbonatoms, or 1 to 3 carbon atoms). An “alkylene” is a divalent alkyl group.

The term “alkenyl,” as used herein, alone or in combination with othergroups, refers to a straight chain or branched hydrocarbon residuehaving a carbon-carbon double bond and having 2 to 20 carbon atoms(e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbonatoms). An “alkenylene” is a divalent alkenyl group.

The term “alkynyl,” as used herein, alone or in combination with othergroups, refers to a straight chain or branched hydrocarbon residuehaving a carbon-carbon triple bond and having 2 to 20 carbon atoms(e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbonatoms). An “alkynylene” is a divalent alkynyl group.

The term “amino,” as used herein, represents —N(R^(N1))₂, wherein eachR^(N1) is, independently, H, OH, NO₂, N(R^(N2))₂, SO₂OR^(N2), SO₂R^(N2),SOR^(N2), an N-protecting group, alkyl, alkoxy, aryl, arylalkyl,cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others describedherein), wherein each of these recited R^(N1) groups can be optionallysubstituted; or two R^(N1) combine to form an alkylene orheteroalkylene, and wherein each R^(N2) is, independently, H, alkyl, oraryl. The amino groups of the compounds described herein can be anunsubstituted amino (i.e., —NH₂) or a substituted amino (i.e.,—N(R^(N1))₂).

The term “aryl,” as used herein, refers to an aromatic mono- orpolycarbocyclic radical of, e.g., 6 to 12, carbon atoms having at leastone aromatic ring. Examples of such groups include, but are not limitedto, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl,indanyl, and 1H-indenyl.

The term “arylalkyl,” as used herein, represents an alkyl groupsubstituted with an aryl group. Exemplary unsubstituted arylalkyl groupsare from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons,such as C₁-C₆ alkyl C₆-C₁₀ aryl, C₁-C₁₀ alkyl C₆-C₁₀ aryl, or C₁-C₂₀alkyl C₆-C₁₀ aryl), such as, benzyl and phenethyl. In some embodiments,the alkyl and the aryl each can be further substituted with 1, 2, 3, or4 substituent groups as defined herein for the respective groups.

The term “azido,” as used herein, represents a —N₃ group.

The term “bridged cyclyl,” as used herein, refers to a bridgedpolycyclic group of 5 to 20 atoms, containing from 1 to 3 bridges.Bridged cyclyl includes bridged carbocyclyl (e.g., norbornyl) andbridged heterocyclyl (e.g., 1,4-diazabicyclo[2.2.2]octane).

The term “cyano,” as used herein, represents a —CN group.

The term “carbocyclyl,” as used herein, refers to a non-aromatic C₃-C₁₂,monocyclic or polycyclic (e.g., bicyclic or tricyclic) structure inwhich the rings are formed by carbon atoms. Carbocyclyl structuresinclude cycloalkyl groups (e.g., cyclohexyl) and unsaturated carbocyclylradicals (e.g., cyclohexenyl). Polycyclic carbocyclyl includesspirocyclic carbocyclyl, bridged carbocyclyl, and fused carbocyclyl. A“carbocyclylene” is a divalent carbocyclyl group.

The term “cycloalkyl,” as used herein, refers to a saturated,non-aromatic, monovalent mono- or polycarbocyclic radical of 3 to 10,preferably 3 to 6 carbon atoms. This term is further exemplified byradicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, and adamantyl.

The terms “halo” or “halogen,” as used herein, mean a fluorine (fluoro),chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkyl groups. Examples ofheteroalkyl groups are an “alkoxy” which, as used herein, refers toalkyl-O— (e.g., methoxy and ethoxy), and an “alkylamino” which, as usedherein, refers to —N(alkyl)R^(Na), where R^(Na) is H or alkyl (e.g.,methylamino). A “heteroalkylene” is a divalent heteroalkyl group.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkenyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkenyl groups. Examples ofheteroalkenyl groups are an “alkenoxy” which, as used herein, refers toalkenyl-O—. A “heteroalkenylene” is a divalent heteroalkenyl group.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkynyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkynyl groups. Examples ofheteroalkynyl groups are an “alkynoxy” which, as used herein, refers toalkynyl-O—. A “heteroalkynylene” is a divalent heteroalkynyl group.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor polycyclic structure of 5 to 12 atoms having at least one aromaticring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen,and sulfur, with the remaining ring atoms being carbon. One or two ringcarbon atoms of the heteroaryl group may be replaced with a carbonylgroup. Examples of heteroaryl groups are pyridyl, pyrazoyl,benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl,and thiazolyl. A “heteroarylene” is a divalent heteroaryl group.

The term “heteroarylalkyl,” as used herein, represents an alkyl groupsubstituted with a heteroaryl group. Exemplary unsubstitutedheteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 orfrom 7 to 20 carbons, such as C₁-C₆ alkyl C₂-C₉ heteroaryl, C₁-C₁₀ alkylC₂-C₉ heteroaryl, or C₁-C₂₀ alkyl C₂-C₉ heteroaryl). In someembodiments, the alkyl and the heteroaryl each can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein forthe respective groups.

The term “heterocyclyl,” as used herein, refers a monocyclic orpolycyclic radical (e.g., bicyclic or tricyclic) having 3 to 12 atomshaving at least one non-aromatic ring containing 1, 2, 3, or 4 ringatoms selected from N, O, or S, and no aromatic ring containing any N,O, or S atoms. Polycyclic heterocyclyl includes spirocyclicheterocyclyl, bridged heterocyclyl, and fused heterocyclyl. Examples ofheterocyclyl groups include, but are not limited to, morpholinyl,thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A“heterocyclylene” is a divalent heterocyclyl group.

The term “heterocyclylalkyl,” as used herein, represents an alkyl groupsubstituted with a heterocyclyl group. Exemplary unsubstitutedheterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 orfrom 7 to 20 carbons, such as C₁-C₆ alkyl C₂-C₉ heterocyclyl, C₁-C₁₀alkyl C₂-C₉ heterocyclyl, or C₁-C₂₀ alkyl C₂-C₉ heterocyclyl). In someembodiments, the alkyl and the heterocyclyl each can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein forthe respective groups.

The term “hydroxyalkyl,” as used herein, represents alkyl groupsubstituted with an —OH group.

The term “hydroxyl,” as used herein, represents an —OH group.

The term “imine,” as used herein, represents ═NR^(N) group, where R^(N)is, e.g., H or alkyl.

The term “N-protecting group,” as used herein, represents those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used N-protecting groups are disclosed inGreene, “Protective Groups in Organic Synthesis,” 3rd Edition (JohnWiley & Sons, New York, 1999). N-protecting groups include, but are notlimited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotectedD, L, or D, L-amino acids such as alanine, leucine, and phenylalanine;sulfonyl-containing groups such as benzenesulfonyl, andp-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl,arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl,and silyl groups, such as trimethylsilyl. Preferred N-protecting groupsare alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl(Cbz).

The term “nitro,” as used herein, represents an —NO₂ group.

The term “oxo,” as used herein, represents an ═O group.

The term “thiol,” as used herein, represents an —SH group.

The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclylgroups may be substituted or unsubstituted. When substituted, there willgenerally be 1 to 4 substituents present, unless otherwise specified.Substituents include, for example: alkyl (e.g., unsubstituted andsubstituted, where the substituents include any group described herein,e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstitutedphenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl),halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted andunsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl,amino (e.g., NH₂ or mono- or dialkyl amino), azido, cyano, nitro, oxo,sulfonyl, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl,and heterocyclyl groups may also be substituted with alkyl(unsubstituted and substituted such as arylalkyl (e.g., substituted andunsubstituted benzyl)).

Compounds described herein (e.g., compounds of the invention) can haveone or more asymmetric carbon atoms and can exist in the form ofoptically pure enantiomers, mixtures of enantiomers such as, forexample, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, or mixtures ofdiastereoisomeric racemates. The optically active forms can be obtainedfor example by resolution of the racemates, by asymmetric synthesis orasymmetric chromatography (chromatography with a chiral adsorbent oreluant). That is, certain of the disclosed compounds may exist invarious stereoisomeric forms. Stereoisomers are compounds that differonly in their spatial arrangement. Enantiomers are pairs ofstereoisomers whose mirror images are not superimposable, most commonlybecause they contain an asymmetrically substituted carbon atom that actsas a chiral center. “Enantiomer” means one of a pair of molecules thatare mirror images of each other and are not superimposable.Diastereomers are stereoisomers that are not related as mirror images,most commonly because they contain two or more asymmetricallysubstituted carbon atoms and represent the configuration of substituentsaround one or more chiral carbon atoms. Enantiomers of a compound can beprepared, for example, by separating an enantiomer from a racemate usingone or more well-known techniques and methods, such as, for example,chiral chromatography and separation methods based thereon. Theappropriate technique and/or method for separating an enantiomer of acompound described herein from a racemic mixture can be readilydetermined by those of skill in the art. “Racemate” or “racemic mixture”means a compound containing two enantiomers, wherein such mixturesexhibit no optical activity; i.e., they do not rotate the plane ofpolarized light. “Geometric isomer” means isomers that differ in theorientation of substituent atoms in relationship to a carbon-carbondouble bond, to a cycloalkyl ring, or to a bridged bicyclic system.Atoms (other than H) on each side of a carbon-carbon double bond may bein an E (substituents are on opposite sides of the carbon-carbon doublebond) or Z (substituents are oriented on the same side) configuration.“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicateconfigurations relative to the core molecule. Certain of the disclosedcompounds may exist in atropisomeric forms. Atropisomers arestereoisomers resulting from hindered rotation about single bonds wherethe steric strain barrier to rotation is high enough to allow for theisolation of the conformers. The compounds described herein (e.g., thecompounds of the invention) may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods. When the stereochemistry of a disclosedcompound is named or depicted by structure, the named or depictedstereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weightrelative to the other stereoisomers. When a single enantiomer is namedor depicted by structure, the depicted or named enantiomer is at least60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When asingle diastereomer is named or depicted by structure, the depicted ornamed diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% byweight pure. Percent optical purity is the ratio of the weight of theenantiomer or over the weight of the enantiomer plus the weight of itsoptical isomer. Diastereomeric purity by weight is the ratio of theweight of one diastereomer or over the weight of all the diastereomers.When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure relative to the otherstereoisomers. When a single enantiomer is named or depicted bystructure, the depicted or named enantiomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer isnamed or depicted by structure, the depicted or named diastereomer is atleast 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percentpurity by mole fraction is the ratio of the moles of the enantiomer orover the moles of the enantiomer plus the moles of its optical isomer.Similarly, percent purity by moles fraction is the ratio of the moles ofthe diastereomer or over the moles of the diastereomer plus the moles ofits isomer. When a disclosed compound is named or depicted by structurewithout indicating the stereochemistry, and the compound has at leastone chiral center, it is to be understood that the name or structureencompasses either enantiomer of the compound free from thecorresponding optical isomer, a racemic mixture of the compound, ormixtures enriched in one enantiomer relative to its correspondingoptical isomer. When a disclosed compound is named or depicted bystructure without indicating the stereochemistry and has two or morechiral centers, it is to be understood that the name or structureencompasses a diastereomer free of other diastereomers, a number ofdiastereomers free from other diastereomeric pairs, mixtures ofdiastereomers, mixtures of diastereomeric pairs, mixtures ofdiastereomers in which one diastereomer is enriched relative to theother diastereomer(s), or mixtures of diastereomers in which one or morediastereomer is enriched relative to the other diastereomers. Theinvention embraces all of these forms.

Compounds of the present disclosure also include all of the isotopes ofthe atoms occurring in the intermediate or final compounds. “Isotopes”refers to atoms having the same atomic number but different mass numbersresulting from a different number of neutrons in the nuclei. Forexample, isotopes of hydrogen include tritium and deuterium.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Isotopically-labeled compounds(e.g., those labeled with ³H and ¹⁴C) can be useful in compound orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, one or more hydrogenatoms are replaced by ²H or ³H, or one or more carbon atoms are replacedby ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Preparations ofisotopically labelled compounds are known to those of skill in the art.For example, isotopically labeled compounds can generally be prepared byfollowing procedures analogous to those disclosed for compounds of thepresent invention described herein, by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

As is known in the art, many chemical entities can adopt a variety ofdifferent solid forms such as, for example, amorphous forms orcrystalline forms (e.g., polymorphs, hydrates, solvate). In someembodiments, compounds of the present invention may be utilized in anysuch form, including in any solid form. In some embodiments, compoundsdescribed or depicted herein may be provided or utilized in hydrate orsolvate form.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present disclosure; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Definitions

In this application, unless otherwise clear from context, (i) the term“a” may be understood to mean “at least one”; (ii) the term “or” may beunderstood to mean “and/or”; and (iii) the terms “including” and“including” may be understood to encompass itemized components or stepswhether presented by themselves or together with one or more additionalcomponents or steps.

As used herein, the terms “about” and “approximately” refer to a valuethat is within 10% above or below the value being described. Forexample, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

As used herein, the term “administration” refers to the administrationof a composition (e.g., a compound or a preparation that includes acompound as described herein) to a subject or system. Administration toan animal subject (e.g., to a human) may be by any appropriate route.For example, in some embodiments, administration may be bronchial(including by bronchial instillation), buccal, enteral, interdermal,intra-arterial, intradermal, intragastric, intramedullary,intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral,intravenous, intraventricular, mucosal, nasal, oral, rectal,subcutaneous, sublingual, topical, tracheal (including by intratrachealinstillation), transdermal, vaginal, and vitreal.

As used herein, the term “adult soft tissue sarcoma” refers to a sarcomathat develops in the soft tissues of the body, typically in adolescentand adult subjects (e.g., subjects who are at least 10 years old, 11years old, 12 years old, 13 years old, 14 years old, 15 years old, 16years old, 17 years old, 18 years old, or 19 years old). Non-limitingexamples of adult soft tissue sarcoma include, but are not limited to,synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma,dermatofibrosarcoma, liposarcoma, leiomyosarcoma, hemangiosarcoma,Kaposi's sarcoma, lymphangiosarcoma, malignant peripheral nerve sheathtumor/neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletalosteosarcoma, extraskeletal myxoid chondrosarcoma, and extraskeletalmesenchymal.

The term “antisense,” as used herein, refers to a nucleic acidcomprising a polynucleotide that is sufficiently complementary to all ora portion of a gene, primary transcript, or processed mRNA, so as tointerfere with expression of the endogenous gene (e.g., BRD9).“Complementary” polynucleotides are those that are capable of basepairing according to the standard Watson-Crick complementarity rules.Specifically, purines will base pair with pyrimidines to form acombination of guanine paired with cytosine (G:C) and adenine pairedwith either thymine (A:T) in the case of DNA, or adenine paired withuracil (A:U) in the case of RNA. It is understood that twopolynucleotides may hybridize to each other even if they are notcompletely complementary to each other, provided that each has at leastone region that is substantially complementary to the other.

The term “antisense nucleic acid” includes single-stranded RNA as wellas double-stranded DNA expression cassettes that can be transcribed toproduce an antisense RNA. “Active” antisense nucleic acids are antisenseRNA molecules that are capable of selectively hybridizing with a primarytranscript or mRNA encoding a polypeptide having at least 80% sequenceidentity (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) with the targetedpolypeptide sequence (e.g., a BRD9 polypeptide sequence). The antisensenucleic acid can be complementary to an entire coding strand, or to onlya portion thereof. In some embodiments, an antisense nucleic acidmolecule is antisense to a “coding region” of the coding strand of anucleotide sequence. The term “coding region” refers to the region ofthe nucleotide sequence comprising codons that are translated into aminoacid residues. In some embodiments, the antisense nucleic acid moleculeis antisense to a “noncoding region” of the coding strand of anucleotide sequence. The term “noncoding region” refers to 5′ and 3′sequences that flank the coding region that are not translated intoamino acids (i.e., also referred to as 5′ and 3′ untranslated regions).The antisense nucleic acid molecule can be complementary to the entirecoding region of mRNA, or can be antisense to only a portion of thecoding or noncoding region of an mRNA. For example, the antisenseoligonucleotide can be complementary to the region surrounding thetranslation start site. An antisense oligonucleotide can be, forexample, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides inlength.

As used herein, the term “BAF complex” refers to the BRG1- orHRBM-associated factors complex in a human cell.

As used herein, the term “BAF complex-related disorder” refers to adisorder that is caused or affected by the level and/or activity of aBAF complex.

As used herein, the terms “GBAF complex” and “GBAF” refer to a SWI/SNFATPase chromatin remodeling complex in a human cell. GBAF complexsubunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B,BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2,SMARCD3, and SS18. The term “cancer” refers to a condition caused by theproliferation of malignant neoplastic cells, such as tumors, neoplasms,carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, the term “BRD9” refers to bromodomain-containing protein9, a component of the BAF (BRG1- or BRM-associated factors) complex, aSWI/SNF ATPase chromatin remodeling complex, and belongs to family IV ofthe bromodomain-containing proteins. BRD9 is encoded by the BRD9 gene,the nucleic acid sequence of which is set forth in SEQ ID NO: 1. Theterm “BRD9” also refers to natural variants of the wild-type BRD9protein, such as proteins having at least 85% identity (e.g., 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%identity, or more) to the amino acid sequence of wild-type BRD9, whichis set forth in SEQ ID NO: 2.

As used herein, the term “BRD9-related disorder” refers to a disorderthat is caused or affected by the level and/or activity of BRD9. Theterm “cancer” refers to a condition caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, and lymphomas.

As used herein, a “combination therapy” or “administered in combination”means that two (or more) different agents or treatments are administeredto a subject as part of a defined treatment regimen for a particulardisease or condition. The treatment regimen defines the doses andperiodicity of administration of each agent such that the effects of theseparate agents on the subject overlap. In some embodiments, thedelivery of the two or more agents is simultaneous or concurrent and theagents may be co-formulated. In some embodiments, the two or more agentsare not co-formulated and are administered in a sequential manner aspart of a prescribed regimen. In some embodiments, administration of twoor more agents or treatments in combination is such that the reductionin a symptom, or other parameter related to the disorder is greater thanwhat would be observed with one agent or treatment delivered alone or inthe absence of the other. The effect of the two treatments can bepartially additive, wholly additive, or greater than additive (e.g.,synergistic). Sequential or substantially simultaneous administration ofeach therapeutic agent can be effected by any appropriate routeincluding, but not limited to, oral routes, intravenous routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents can be administered by the same route orby different routes. For example, a first therapeutic agent of thecombination may be administered by intravenous injection while a secondtherapeutic agent of the combination may be administered orally.

A “compound of the present invention” and similar terms as used herein,whether explicitly noted or not, refers to compounds useful for treatingBAF-related disorders (e.g., cancer or infection) described herein,including, e.g., compounds of Formula I (e.g., compounds of Table 1A,Table 1B, and Table 1D) and compounds of Table 1C and 1E, as well assalts (e.g., pharmaceutically acceptable salts), solvates, hydrates,stereoisomers (including atropisomers), and tautomers thereof. Thoseskilled in the art will appreciate that certain compounds describedherein can exist in one or more different isomeric (e.g., stereoisomers,geometric isomers, atropisomers, and tautomers) or isotopic (e.g., inwhich one or more atoms has been substituted with a different isotope ofthe atom, such as hydrogen substituted for deuterium) forms. Unlessotherwise indicated or clear from context, a depicted structure can beunderstood to represent any such isomeric or isotopic form, individuallyor in combination. Compounds described herein can be asymmetric (e.g.,having one or more stereocenters). All stereoisomers, such asenantiomers and diastereomers, are intended unless otherwise indicated.Compounds of the present disclosure that contain asymmetricallysubstituted carbon atoms can be isolated in optically active or racemicforms. Methods on how to prepare optically active forms from opticallyactive starting materials are known in the art, such as by resolution ofracemic mixtures or by stereoselective synthesis. Many geometric isomersof olefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present disclosure. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, one or more compounds depicted herein may exist indifferent tautomeric forms. As will be clear from context, unlessexplicitly excluded, references to such compounds encompass all suchtautomeric forms. In some embodiments, tautomeric forms result from theswapping of a single bond with an adjacent double bond and theconcomitant migration of a proton. In certain embodiments, a tautomericform may be a prototropic tautomer, which is an isomeric protonationstates having the same empirical formula and total charge as a referenceform. Examples of moieties with prototropic tautomeric forms areketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs,amide-imidic acid pairs, enamine-imine pairs, and annular forms where aproton can occupy two or more positions of a heterocyclic system, suchas, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.

In some embodiments, tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution. In certainembodiments, tautomeric forms result from acetal interconversion.

As used herein, the term “degrader” refers to a small molecule compoundincluding a degradation moiety, wherein the compound interacts with aprotein (e.g., BRD9) in a way which results in degradation of theprotein, e.g., binding of the compound results in at least 5% reductionof the level of the protein, e.g., in a cell or subject.

As used herein, the term “degradation moiety” refers to a moiety whosebinding results in degradation of a protein, e.g., BRD9. In one example,the moiety binds to a protease or a ubiquitin ligase that metabolizesthe protein, e.g., BRD9.

By “determining the level of a protein” is meant the detection of aprotein, or an mRNA encoding the protein, by methods known in the arteither directly or indirectly. “Directly determining” means performing aprocess (e.g., performing an assay or test on a sample or “analyzing asample” as that term is defined herein) to obtain the physical entity orvalue. “Indirectly determining” refers to receiving the physical entityor value from another party or source (e.g., a third-party laboratorythat directly acquired the physical entity or value). Methods to measureprotein level generally include, but are not limited to, westernblotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA),radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surfaceplasmon resonance, chemiluminescence, fluorescent polarization,phosphorescence, immunohistochemical analysis, matrix-assisted laserdesorption/ionization time-of-flight (MALDI-TOF) mass spectrometry,liquid chromatography (LC)-mass spectrometry, microcytometry,microscopy, fluorescence activated cell sorting (FACS), and flowcytometry, as well as assays based on a property of a protein including,but not limited to, enzymatic activity or interaction with other proteinpartners. Methods to measure mRNA levels are known in the art.

As used herein, the terms “effective amount,” “therapeutically effectiveamount,” and “a “sufficient amount” of an agent that reduces the leveland/or activity of BRD9 (e.g., in a cell or a subject) described hereinrefer to a quantity sufficient to, when administered to the subject,including a human, effect beneficial or desired results, includingclinical results, and, as such, an “effective amount” or synonym theretodepends on the context in which it is being applied. For example, in thecontext of treating cancer, it is an amount of the agent that reducesthe level and/or activity of BRD9 sufficient to achieve a treatmentresponse as compared to the response obtained without administration ofthe agent that reduces the level and/or activity of BRD9. The amount ofa given agent that reduces the level and/or activity of BRD9 describedherein that will correspond to such an amount will vary depending uponvarious factors, such as the given agent, the pharmaceuticalformulation, the route of administration, the type of disease ordisorder, the identity of the subject (e.g., age, sex, and/or weight) orhost being treated, and the like, but can nevertheless be routinelydetermined by one of skill in the art. Also, as used herein, a“therapeutically effective amount” of an agent that reduces the leveland/or activity of BRD9 of the present disclosure is an amount whichresults in a beneficial or desired result in a subject as compared to acontrol. As defined herein, a therapeutically effective amount of anagent that reduces the level and/or activity of BRD9 of the presentdisclosure may be readily determined by one of ordinary skill by routinemethods known in the art. Dosage regimen may be adjusted to provide theoptimum therapeutic response.

As used herein, the term “inhibitor” refers to any agent which reducesthe level and/or activity of a protein (e.g., BRD9). Non-limitingexamples of inhibitors include small molecule inhibitors, degraders,antibodies, enzymes, or polynucleotides (e.g., siRNA).

The term “inhibitory RNA agent” refers to an RNA, or analog thereof,having sufficient sequence complementarity to a target RNA to direct RNAinterference. Examples also include a DNA that can be used to make theRNA. RNA interference (RNAi) refers to a sequence-specific or selectiveprocess by which a target molecule (e.g., a target gene, protein, orRNA) is down-regulated. Generally, an interfering RNA (“iRNA”) is adouble-stranded short-interfering RNA (siRNA), short hairpin RNA(shRNA), or single-stranded micro-RNA (miRNA) that results in catalyticdegradation of specific mRNAs, and also can be used to lower or inhibitgene expression.

By “level” is meant a level of a protein, or mRNA encoding the protein,as compared to a reference. The reference can be any useful reference,as defined herein. By a “decreased level” or an “increased level” of aprotein is meant a decrease or increase in protein level, as compared toa reference (e.g., a decrease or an increase by about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 100%, about 150%,about 200%, about 300%, about 400%, about 500%, or more; a decrease oran increase of more than about 10%, about 15%, about 20%, about 50%,about 75%, about 100%, or about 200%, as compared to a reference; adecrease or an increase by less than about 0.01-fold, about 0.02-fold,about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less;or an increase by more than about 1.2-fold, about 1.4-fold, about1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold,about 20-fold, about 30-fold, about 40-fold, about 50-fold, about100-fold, about 1000-fold, or more). A level of a protein may beexpressed in mass/vol (e.g., g/dL, mg/mL, μg/mL, ng/mL) or percentagerelative to total protein or mRNA in a sample.

The terms “miRNA” and “microRNA” refer to an RNA agent, preferably asingle-stranded agent, of about 10-50 nucleotides in length, preferablybetween about 15-25 nucleotides in length, which is capable of directingor mediating RNA interference. Naturally-occurring miRNAs are generatedfrom stem-loop precursor RNAs (i.e., pre-miRNAs) by Dicer. The term“Dicer” as used herein, includes Dicer as well as any Dicer ortholog orhomolog capable of processing dsRNA structures into siRNAs, miRNAs,siRNA-like or miRNA-like molecules. The term microRNA (“miRNA”) is usedinterchangeably with the term “small temporal RNA” (“stRNA”) based onthe fact that naturally-occurring miRNAs have been found to be expressedin a temporal fashion (e.g., during development).

By “modulating the activity of a BAF complex,” is meant altering thelevel of an activity related to a BAF complex (e.g., GBAF), or a relateddownstream effect. The activity level of a BAF complex may be measuredusing any method known in the art, e.g., the methods described in Kadochet al, Cell 153:71-85 (2013), the methods of which are hereinincorporated by reference.

“Percent (%) sequence identity” with respect to a referencepolynucleotide or polypeptide sequence is defined as the percentage ofnucleic acids or amino acids in a candidate sequence that are identicalto the nucleic acids or amino acids in the reference polynucleotide orpolypeptide sequence, after aligning the sequences and introducing gaps,if necessary, to achieve the maximum percent sequence identity.Alignment for purposes of determining percent nucleic acid or amino acidsequence identity can be achieved in various ways that are within thecapabilities of one of skill in the art, for example, using publiclyavailable computer software such as BLAST, BLAST-2, or Megalignsoftware. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.For example, percent sequence identity values may be generated using thesequence comparison computer program BLAST. As an illustration, thepercent sequence identity of a given nucleic acid or amino acidsequence, A, to, with, or against a given nucleic acid or amino acidsequence, B, (which can alternatively be phrased as a given nucleic acidor amino acid sequence, A that has a certain percent sequence identityto, with, or against a given nucleic acid or amino acid sequence, B) iscalculated as follows:

100 multiplied by (the fraction X/Y)

where X is the number of nucleotides or amino acids scored as identicalmatches by a sequence alignment program (e.g., BLAST) in that program'salignment of A and B, and where Y is the total number of nucleic acidsin B. It will be appreciated that where the length of nucleic acid oramino acid sequence A is not equal to the length of nucleic acid oramino acid sequence B, the percent sequence identity of A to B will notequal the percent sequence identity of B to A.

A “pharmaceutically acceptable excipient,” as used herein, refers anyingredient other than the compounds described herein (for example, avehicle capable of suspending or dissolving the active compound) andhaving the properties of being substantially nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, and waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A,vitamin E, vitamin C, and xylitol.

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of any of the compoundsdescribed herein. For example, pharmaceutically acceptable salts of anyof the compounds described herein include those that are within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and animals without undue toxicity, irritation,allergic response and are commensurate with a reasonable benefit/riskratio. Pharmaceutically acceptable salts are well known in the art. Forexample, pharmaceutically acceptable salts are described in: Berge etal., J. Pharmaceutical Sciences 66:1-19, 1977 and in PharmaceuticalSalts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during thefinal isolation and purification of the compounds described herein orseparately by reacting a free base group with a suitable organic acid.

The compounds described herein may have ionizable groups so as to becapable of preparation as pharmaceutically acceptable salts. These saltsmay be acid addition salts involving inorganic or organic acids or thesalts may, in the case of acidic forms of the compounds describedherein, be prepared from inorganic or organic bases. Frequently, thecompounds are prepared or used as pharmaceutically acceptable saltsprepared as addition products of pharmaceutically acceptable acids orbases. Suitable pharmaceutically acceptable acids and bases and methodsfor preparation of the appropriate salts are well-known in the art.Salts may be prepared from pharmaceutically acceptable non-toxic acidsand bases including inorganic and organic acids and bases.Representative acid addition salts include acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, undecanoate, and valeratesalts. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, and magnesium, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, andethylamine.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other pharmaceutically acceptable formulation.

By “reducing the activity of BRD9,” is meant decreasing the level of anactivity related to an BRD9, or a related downstream effect. Anon-limiting example of inhibition of an activity of BRD9 is decreasingthe level of a BAF complex (e.g., GBAF) in a cell. The activity level ofBRD9 may be measured using any method known in the art. In someembodiments, an agent which reduces the activity of BRD9 is a smallmolecule BRD9 inhibitor. In some embodiments, an agent which reduces theactivity of BRD9 is a small molecule BRD9 degrader.

By “reducing the level of BRD9,” is meant decreasing the level of BRD9in a cell or subject. The level of BRD9 may be measured using any methodknown in the art.

By a “reference” is meant any useful reference used to compare proteinor mRNA levels. The reference can be any sample, standard, standardcurve, or level that is used for comparison purposes. The reference canbe a normal reference sample or a reference standard or level. A“reference sample” can be, for example, a control, e.g., a predeterminednegative control value such as a “normal control” or a prior sampletaken from the same subject; a sample from a normal healthy subject,such as a normal cell or normal tissue; a sample (e.g., a cell ortissue) from a subject not having a disease; a sample from a subjectthat is diagnosed with a disease, but not yet treated with a compounddescribed herein; a sample from a subject that has been treated by acompound described herein; or a sample of a purified protein (e.g., anydescribed herein) at a known normal concentration. By “referencestandard or level” is meant a value or number derived from a referencesample. A “normal control value” is a pre-determined value indicative ofnon-disease state, e.g., a value expected in a healthy control subject.Typically, a normal control value is expressed as a range (“between Xand Y”), a high threshold (“no higher than X”), or a low threshold (“nolower than X”). A subject having a measured value within the normalcontrol value for a particular biomarker is typically referred to as“within normal limits” for that biomarker. A normal reference standardor level can be a value or number derived from a normal subject nothaving a disease or disorder (e.g., cancer); a subject that has beentreated with a compound described herein. In preferred embodiments, thereference sample, standard, or level is matched to the sample subjectsample by at least one of the following criteria: age, weight, sex,disease stage, and overall health. A standard curve of levels of apurified protein, e.g., any described herein, within the normalreference range can also be used as a reference.

The terms “short interfering RNA” and “siRNA” (also known as “smallinterfering RNAs”) refer to an RNA agent, preferably a double-strandedagent, of about 10-50 nucleotides in length, the strands optionallyhaving overhanging ends comprising, for example 1, 2 or 3 overhangingnucleotides (or nucleotide analogs), which is capable of directing ormediating RNA interference. Naturally-occurring siRNAs are generatedfrom longer dsRNA molecules (e.g., >25 nucleotides in length) by acell's RNAi machinery (e.g., Dicer or a homolog thereof).

The term “shRNA”, as used herein, refers to an RNA agent having astem-loop structure, comprising a first and second region ofcomplementary sequence, the degree of complementarity and orientation ofthe regions being sufficient such that base pairing occurs between theregions, the first and second regions being joined by a loop region, theloop resulting from a lack of base pairing between nucleotides (ornucleotide analogs) within the loop region.

As used herein, the term “subject” refers to any organism to which acomposition in accordance with the invention may be administered, e.g.,for experimental, diagnostic, prophylactic, and/or therapeutic purposes.Typical subjects include any animal (e.g., mammals such as mice, rats,rabbits, non-human primates, and humans). A subject may seek or be inneed of treatment, require treatment, be receiving treatment, bereceiving treatment in the future, or be a human or animal who is undercare by a trained professional for a particular disease or condition.

As used herein, the term “SS18-SSX fusion protein-related disorder”refers to a disorder that is caused or affected by the level and/oractivity of SS18-SSX fusion protein.

As used herein, the terms “treat,” “treated,” or “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms; diminishmentof the extent of a condition, disorder, or disease; stabilized (i.e.,not worsening) state of condition, disorder, or disease; delay in onsetor slowing of condition, disorder, or disease progression; ameliorationof the condition, disorder, or disease state or remission (whetherpartial or total), whether detectable or undetectable; an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient; or enhancement or improvement of condition,disorder, or disease. Treatment includes eliciting a clinicallysignificant response without excessive levels of side effects. Treatmentalso includes prolonging survival as compared to expected survival ifnot receiving treatment.

As used herein, the terms “variant” and “derivative” are usedinterchangeably and refer to naturally-occurring, synthetic, andsemi-synthetic analogues of a compound, peptide, protein, or othersubstance described herein. A variant or derivative of a compound,peptide, protein, or other substance described herein may retain orimprove upon the biological activity of the original material.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a series of graphs illustrating the effect of specific guideRNA (sgRNA) targeting of the BRD9 BAF complex subunit on synovialsarcoma cell growth. The Y-axis indicated the dropout ratio. The X-axisindicates the nucleotide position of the BRD9 gene. The grey boxindicates the range of the negative control sgRNAs in the screen. TheSYO1 cell line carries SS18-SSX2 fusion protein. The breakpoint joiningthe N-terminal region of SS18 to the C-terminal region of SSX2 areindicated by the black lines in their respective panel. The linearprotein sequence is show with BRD9 PFAM domains annotated from the PFAMdatabase.

FIG. 2 is an image illustrating dose dependent depletion of BRD9 levelsin a synovial sarcoma cell line (SYO1) in the presence of a BRD9degrader.

FIG. 3 is an image illustrating sustained suppression of BRD9 levels ina synovial sarcoma cell line (SYO1) in the presence of a BRD9 degraderover 72 hours.

FIG. 4 is an image illustrating sustained suppression of BRD9 levels intwo cell lines (293T and SYO1) in the presence of a BRD9 degrader over 5days.

FIG. 5 is an image illustrating sustained suppression of BRD9 levels insynovial sarcoma cell lines (SYO1 and Yamato) in the presence of a BRD9degrader over 7 days compared to the levels in cells treated with CRISPRreagents.

FIG. 6 is an image illustrating the effect on cell growth of six celllines (SYO1, Yamato, A549, HS-SY-II, ASKA, and 293T) in the presence ofa BRD9 degrader and a BRD9 inhibitor.

FIG. 7 is an image illustrating the effect on cell growth of two celllines (SYO1 and G401) in the presence of a BRD9 degrader.

FIG. 8 is an image illustrating the effect on cell growth of threesynovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presenceof a BRD9 degrader, BRD9 binder and E3 ligase binder.

FIG. 9 is an image illustrating the effect on cell growth of threenon-synovial sarcoma cell lines (RD, HCT116, and Calu6) in the presenceof a BRD9 degrader, BRD9 binder and E3 ligase binder.

FIG. 10 is a graph illustrating the percentage of SYO1 in various cellcycle phases following treatment with DMSO, Compound 1 at 200 nM, orCompound 1 at 1 μM for 8 or 13 days.

FIG. 11 is a series of contour plots illustrating the percentage of SYO1cells in various cell cycle phases following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for8 days. Numerical values corresponding to each contour plot are found inthe table below.

FIG. 12 is a series of contour plots illustrating the percentage of SYO1cells in various cell cycle phases following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for13 days. Numerical values corresponding to each contour plot are foundin the table below.

FIG. 13 is a series of contour plots illustrating the percentage ofearly- and late-apoptotic SYO1 cells following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for8 days. Numerical values corresponding to each contour plot are found inthe table below.

FIG. 14 is a graph illustrating the proteins present in BAF complexesincluding the SS18-SSX fusion protein.

DETAILED DESCRIPTION

The present disclosure features compositions and methods useful for thetreatment of BAF-related disorders (e.g., cancer and infection). Thedisclosure further features compositions and methods useful forinhibition of the level and/or activity of BRD9, e.g., for the treatmentof disorders such as cancer (e.g., sarcoma) and infection (e.g., viralinfection), e.g., in a subject in need thereof.

Compounds

Compounds described herein reduce the level of an activity related toBRD9, or a related downstream effect, or reduce the level of BRD9 in acell or subject. Exemplary compounds described herein have the structureaccording to Formula I.

Formula I is

A-L-B  Formula I,

-   -   where    -   A is a BRD9 binding moiety;    -   B is a degradation moiety; and    -   L has the structure of Formula II:

A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)—(F³)_(o2)-(E²)_(p)-A²,  FormulaII

-   -   wherein    -   A¹ is a bond between the linker and A;    -   A² is a bond between B and the linker;    -   each of m, n, o1, o2, and p is, independently, 0 or 1;    -   each of E¹ and E² is, independently, O, S, NR^(N), optionally        substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl,        optionally substituted C₂₋₁₀ alkynyl, optionally substituted        C₂-C₁₀ polyethylene glycol, or optionally substituted C₁₋₁₀        heteroalkyl;    -   E³ is O, S, or NR^(N);    -   each R^(N) is, independently, H, optionally substituted C₁₋₄        alkyl, optionally substituted C₂₋₄ alkenyl, optionally        substituted C₂₋₄ alkynyl, optionally substituted C₂₋₆        heterocyclyl, optionally substituted C₆₋₁₂ aryl, or optionally        substituted C₁₋₇ heteroalkyl;    -   C₃ is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and    -   each of F¹, F², and F³ is, independently, optionally substituted        C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,        optionally substituted C₆-C₁₀ aryl, or optionally substituted        C₂-C₉ heteroaryl, or a pharmaceutically acceptable salt thereof.

Pharmaceutical Uses

The compounds described herein are useful in the methods of theinvention and, while not bound by theory, are believed to exert theirdesirable effects through their ability to modulate the level, status,and/or activity of a BAF complex, e.g., by inhibiting the activity orlevel of the BRD9 protein in a cell within the BAF complex in a mammal.

An aspect of the present invention relates to methods of treatingdisorders related to BRD9 such as cancer in a subject in need thereof.In some embodiments, the compound is administered in an amount and for atime effective to result in one of (or more, e.g., two or more, three ormore, four or more of): (a) reduced tumor size, (b) reduced rate oftumor growth, (c) increased tumor cell death (d) reduced tumorprogression, (e) reduced number of metastases, (f) reduced rate ofmetastasis, (g) decreased tumor recurrence (h) increased survival ofsubject, and (i) increased progression free survival of a subject.

Treating cancer can result in a reduction in size or volume of a tumor.For example, after treatment, tumor size is reduced by 5% or greater(e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relativeto its size prior to treatment. Size of a tumor may be measured by anyreproducible means of measurement. For example, the size of a tumor maybe measured as a diameter of the tumor.

Treating cancer may further result in a decrease in number of tumors.For example, after treatment, tumor number is reduced by 5% or greater(e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relativeto number prior to treatment. Number of tumors may be measured by anyreproducible means of measurement, e.g., the number of tumors may bemeasured by counting tumors visible to the naked eye or at a specifiedmagnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

Treating cancer can result in a decrease in number of metastatic nodulesin other tissues or organs distant from the primary tumor site. Forexample, after treatment, the number of metastatic nodules is reduced by5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% orgreater) relative to number prior to treatment. The number of metastaticnodules may be measured by any reproducible means of measurement. Forexample, the number of metastatic nodules may be measured by countingmetastatic nodules visible to the naked eye or at a specifiedmagnification (e.g., 2×, 10×, or 50×).

Treating cancer can result in an increase in average survival time of apopulation of subjects treated according to the present invention incomparison to a population of untreated subjects. For example, theaverage survival time is increased by more than 30 days (more than 60days, 90 days, or 120 days). An increase in average survival time of apopulation may be measured by any reproducible means. An increase inaverage survival time of a population may be measured, for example, bycalculating for a population the average length of survival followinginitiation of treatment with the compound described herein. An increasein average survival time of a population may also be measured, forexample, by calculating for a population the average length of survivalfollowing completion of a first round of treatment with apharmaceutically acceptable salt of a compound described herein.

Treating cancer can also result in a decrease in the mortality rate of apopulation of treated subjects in comparison to an untreated population.For example, the mortality rate is decreased by more than 2% (e.g., morethan 5%, 10%, or 25%). A decrease in the mortality rate of a populationof treated subjects may be measured by any reproducible means, forexample, by calculating for a population the average number ofdisease-related deaths per unit time following initiation of treatmentwith a pharmaceutically acceptable salt of a compound described herein.A decrease in the mortality rate of a population may also be measured,for example, by calculating for a population the average number ofdisease-related deaths per unit time following completion of a firstround of treatment with a pharmaceutically acceptable salt of a compounddescribed herein.

Combination Therapies

A method of the invention can be used alone or in combination with anadditional therapeutic agent, e.g., other agents that treat cancer orsymptoms associated therewith, or in combination with other types oftherapies to treat cancer. In combination treatments, the dosages of oneor more of the therapeutic compounds may be reduced from standarddosages when administered alone. For example, doses may be determinedempirically from drug combinations and permutations or may be deduced byisobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).In this case, dosages of the compounds when combined should provide atherapeutic effect.

In some embodiments, the second therapeutic agent is a chemotherapeuticagent (e.g., a cytotoxic agent or other chemical compound useful in thetreatment of cancer). These include alkylating agents, antimetabolites,folic acid analogs, pyrimidine analogs, purine analogs and relatedinhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics,L-Asparaginase, topoisomerase inhibitors, interferons, platinumcoordination complexes, anthracenedione substituted urea, methylhydrazine derivatives, adrenocortical suppressant,adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens,antiandrogen, and gonadotropin-releasing hormone analog. Also includedis 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin,capecitabine, paclitaxel, and doxetaxel. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicinomegaII (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994));dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antiobiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin, including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®,cremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, IL), andTAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum coordination complexes such as cisplatin, oxaliplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone;teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate;irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid;capecitabine; and pharmaceutically acceptable salts, acids orderivatives of any of the above. Two or more chemotherapeutic agents canbe used in a cocktail to be administered in combination with the firsttherapeutic agent described herein. Suitable dosing regimens ofcombination chemotherapies are known in the art and described in, forexample, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), andDouillard et al., Lancet 355(9209):1041-1047 (2000).

In some embodiments, the second therapeutic agent is a therapeutic agentwhich is a biologic such a cytokine (e.g., interferon or an interleukin(e.g., IL-2)) used in cancer treatment. In some embodiments the biologicis an anti-angiogenic agent, such as an anti-VEGF agent, e.g.,bevacizumab (AVASTIN®). In some embodiments the biologic is animmunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., ahumanized antibody, a fully human antibody, an Fc fusion protein or afunctional fragment thereof) that agonizes a target to stimulate ananti-cancer response, or antagonizes an antigen important for cancer.Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab);SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab);HERCEPTIN@(trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH®(alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab);XOLAIR® (omalizumab); BEXXAR® (tositumomab-I-131); RAPTIVA®(efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI®(natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab);LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumabpegol); SIMPONI® (golimumab); ILARIS@(canakinumab); STELARA®(ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX®(motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab);YERVOY@(ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA®(pertuzumab); KADCYLA® (ado-trastuzumab emtansine); and GAZYVA®(obinutuzumab). Also included are antibody-drug conjugates.

The second agent may be a therapeutic agent which is a non-drugtreatment. For example, the second therapeutic agent is radiationtherapy, cryotherapy, hyperthermia, and/or surgical excision of tumortissue.

The second agent may be a checkpoint inhibitor. In one embodiment, theinhibitor of checkpoint is an inhibitory antibody (e.g., a monospecificantibody such as a monoclonal antibody). The antibody may be, e.g.,humanized or fully human. In some embodiments, the inhibitor ofcheckpoint is a fusion protein, e.g., an Fc-receptor fusion protein. Insome embodiments, the inhibitor of checkpoint is an agent, such as anantibody, that interacts with a checkpoint protein. In some embodiments,the inhibitor of checkpoint is an agent, such as an antibody, thatinteracts with the ligand of a checkpoint protein. In some embodiments,the inhibitor of checkpoint is an inhibitor (e.g., an inhibitoryantibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4antibody or fusion a protein such as ipilimumab/YERVOY® ortremelimumab). In some embodiments, the inhibitor of checkpoint is aninhibitor (e.g., an inhibitory antibody or small molecule inhibitor) ofPD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®;pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint isan inhibitor (e.g., an inhibitory antibody or small molecule inhibitor)of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). Insome embodiments, the inhibitor of checkpoint is an inhibitor (e.g., aninhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2(e.g., a PDL2/Ig fusion protein such as AMP 224). In some embodiments,the inhibitor of checkpoint is an inhibitor (e.g., an inhibitoryantibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4,BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1,CHK2, A2aR, B-7 family ligands, or a combination thereof.

In some embodiments, the anti-cancer therapy is a T cell adoptivetransfer (ACT) therapy. In some embodiments, the T cell is an activatedT cell. The T cell may be modified to express a chimeric antigenreceptor (CAR). CAR modified T (CAR-T) cells can be generated by anymethod known in the art. For example, the CAR-T cells can be generatedby introducing a suitable expression vector encoding the CAR to a Tcell. Prior to expansion and genetic modification of the T cells, asource of T cells is obtained from a subject. T cells can be obtainedfrom a number of sources, including peripheral blood mononuclear cells,bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from asite of infection, ascites, pleural effusion, spleen tissue, and tumors.In certain embodiments of the present invention, any number of T celllines available in the art, may be used. In some embodiments, the T cellis an autologous T cell. Whether prior to or after genetic modificationof the T cells to express a desirable protein (e.g., a CAR), the T cellscan be activated and expanded generally using methods as described, forexample, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964;5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869;7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; andU.S. Patent Application Publication No. 20060121005.

In any of the combination embodiments described herein, the first andsecond therapeutic agents are administered simultaneously orsequentially, in either order. The first therapeutic agent may beadministered immediately, up to 1 hour, up to 2 hours, up to 3 hours, upto 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours,up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours upto 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after thesecond therapeutic agent.

Pharmaceutical Compositions

The pharmaceutical compositions described herein are preferablyformulated into pharmaceutical compositions for administration to humansubjects in a biologically compatible form suitable for administrationin vivo.

The compounds described herein may be used in the form of the free base,in the form of salts, solvates, and as prodrugs. All forms are withinthe methods described herein. In accordance with the methods of theinvention, the described compounds or salts, solvates, or prodrugsthereof may be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds described herein may be administered,for example, by oral, parenteral, buccal, sublingual, nasal, rectal,patch, pump, intratumoral, or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, transepithelial, nasal, intrapulmonary, intrathecal,rectal, and topical modes of administration. Parenteral administrationmay be by continuous infusion over a selected period of time.

A compound described herein may be orally administered, for example,with an inert diluent or with an assimilable edible carrier, or it maybe enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly with thefood of the diet. For oral therapeutic administration, a compounddescribed herein may be incorporated with an excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, and wafers. A compound described herein may also beadministered parenterally. Solutions of a compound described herein canbe prepared in water suitably mixed with a surfactant, such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, DMSO, and mixtures thereof with or withoutalcohol, and in oils. Under ordinary conditions of storage and use,these preparations may contain a preservative to prevent the growth ofmicroorganisms. Conventional procedures and ingredients for theselection and preparation of suitable formulations are described, forexample, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and inThe United States Pharmacopeia: The National Formulary (USP 41 NF36),published in 2018. The pharmaceutical forms suitable for injectable useinclude sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that may be easily administered via syringe. Compositions fornasal administration may conveniently be formulated as aerosols, drops,gels, and powders. Aerosol formulations typically include a solution orfine suspension of the active substance in a physiologically acceptableaqueous or non-aqueous solvent and are usually presented in single ormultidose quantities in sterile form in a sealed container, which cantake the form of a cartridge or refill for use with an atomizing device.Alternatively, the sealed container may be a unitary dispensing device,such as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve which is intended for disposal after use. Where thedosage form includes an aerosol dispenser, it will contain a propellant,which can be a compressed gas, such as compressed air or an organicpropellant, such as fluorochlorohydrocarbon. The aerosol dosage formscan also take the form of a pump-atomizer. Compositions suitable forbuccal or sublingual administration include tablets, lozenges, andpastilles, where the active ingredient is formulated with a carrier,such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositionsfor rectal administration are conveniently in the form of suppositoriescontaining a conventional suppository base, such as cocoa butter. Acompound described herein may be administered intratumorally, forexample, as an intratumoral injection. Intratumoral injection isinjection directly into the tumor vasculature and is specificallycontemplated for discrete, solid, accessible tumors. Local, regional, orsystemic administration also may be appropriate. A compound describedherein may advantageously be contacted by administering an injection ormultiple injections to the tumor, spaced for example, at approximately,1 cm intervals. In the case of surgical intervention, the presentinvention may be used preoperatively, such as to render an inoperabletumor subject to resection. Continuous administration also may beapplied where appropriate, for example, by implanting a catheter into atumor or into tumor vasculature.

The compounds described herein may be administered to an animal, e.g., ahuman, alone or in combination with pharmaceutically acceptablecarriers, as noted herein, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration, and standard pharmaceutical practice.

Dosages

The dosage of the compounds described herein, and/or compositionsincluding a compound described herein, can vary depending on manyfactors, such as the pharmacodynamic properties of the compound; themode of administration; the age, health, and weight of the recipient;the nature and extent of the symptoms; the frequency of the treatment,and the type of concurrent treatment, if any; and the clearance rate ofthe compound in the animal to be treated. One of skill in the art candetermine the appropriate dosage based on the above factors. Thecompounds described herein may be administered initially in a suitabledosage that may be adjusted as required, depending on the clinicalresponse. In general, satisfactory results may be obtained when thecompounds described herein are administered to a human at a daily dosageof, for example, between 0.05 mg and 3000 mg (measured as the solidform). Dose ranges include, for example, between 10-1000 mg (e.g.,50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400,450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of thecompound is administered.

Alternatively, the dosage amount can be calculated using the body weightof the patient. For example, the dose of a compound, or pharmaceuticalcomposition thereof, administered to a patient may range from 0.1-100mg/kg (e.g., 0.1-50 mg/kg (e.g., 0.25-25 mg/kg)). In exemplary,non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g.,0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).

Kits

The invention also features kits including (a) a pharmaceuticalcomposition including an agent that reduces the level and/or activity ofBRD9 in a cell or subject described herein, and (b) a package insertwith instructions to perform any of the methods described herein. Insome embodiments, the kit includes (a) a pharmaceutical compositionincluding an agent that reduces the level and/or activity of BRD9 in acell or subject described herein, (b) an additional therapeutic agent(e.g., an anti-cancer agent), and (c) a package insert with instructionsto perform any of the methods described herein.

EXAMPLES Example 1—High Density Tiling sgRNA Screen Against Human BAFComplex Subunits in Synovial Sarcoma Cell Line SYO1

The following example shows that BRD9 sgRNA inhibits cell growth insynovial sarcoma cells.

Procedure:

To perform high density sgRNA tiling screen, an sgRNA library againstBAF complex subunits was custom synthesized at Cellecta (Mountain View,CA). Sequences of DNA encoding the BRD9-targeting sgRNAs used in thisscreen are listed in Table 2. Negative and positive control sgRNA wereincluded in the library. Negative controls consisted of 200 sgRNAs thatdo not target human genome. The positive controls are sgRNAs targetingessential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1, PCNA, POLR2L,RPL9, and SF3A3). DNA sequences encoding all positive and negativecontrol sgRNAs are listed in Table 3. Procedures for virus production,cell infection, and performing the sgRNA screen were previouslydescribed (Tsherniak et al, Cell 170:564-576 (2017); Munoz et al, CancerDiscovery 6:900-913 (2016)). For each sgRNA, 50 counts were added to thesequencing counts and for each time point the resulting counts werenormalized to the total number of counts. The log 2 of the ratio betweenthe counts (defined as dropout ratio) at day 24 and day 1 post-infectionwas calculated. For negative control sgRNAs, the 2.5 and 97.5 percentileof the log 2 dropout ratio of all non-targeting sgRNAs was calculatedand considered as background (grey box in the graph). Protein domainswere obtained from PFAM regions defined for the UNIPROT identifier:Q9H8M2.

Results:

As shown in FIG. 1 , targeted inhibition of the GBAF complex componentBRD9 by sgRNA resulted in growth inhibition of the SYO1 synovial sarcomacell line. sgRNAs against other components of the BAF complexes resultedin increased proliferation of cells, inhibition of cell growth, or hadno effect on SYO1 cells. These data show that targeting various subunitsof the GBAF complex represents a therapeutic strategy for the treatmentof synovial sarcoma.

TABLE 2 BRD9 sgRNA Library SEQ ID NO Nucleic Acid Sequence 203CAAGAAGCACAAGAAGCACA 204 CTTGTGCTTCTTGCCCATGG 205 CTTCTTGTGCTTCTTGCCCA206 ACAAGAAGCACAAGGCCGAG 207 CTCGTAGGACGAGCGCCACT 208CGAGTGGCGCTCGTCCTACG 209 GAGTGGCGCTCGTCCTACGA 210 AGGCTTCTCCAGGGGCTTGT211 AGATTATGCCGACAAGCCCC 212 ACCTTCAGGACTAGCTTTAG 213AGCTTTAGAGGCTTCTCCAG 214 CTAGCTTTAGAGGCTTCTCC 215 TAGCTTTAGAGGCTTCTCCA216 CTAAAGCTAGTCCTGAAGGT 217 GCCTCTAAAGCTAGTCCTGA 218CTTCACTTCCTCCGACCTTC 219 AAGCTAGTCCTGAAGGTCGG 220 AGTGAAGTGACTGAACTCTC221 GTGACTGAACTCTCAGGATC 222 ATAGTAACTGGAGTCGTGGC 223CATCATAGTAACTGGAGTCG 224 TGACCTGTCATCATAGTAAC 225 ACTCCAGTTACTATGATGAC226 CTTTGTGCCTCTCTCGCTCA 227 GGTCAGACCATGAGCGAGAG 228GAAGAAGAAGAAGTCCGAGA 229 GTCCAGATGCTTCTCCTTCT 230 GTCCGAGAAGGAGAAGCATC231 GGAGAAGCATCTGGACGATG 232 TGAGGAAAGAAGGAAGCGAA 233ATCTGGACGATGAGGAAAGA 234 AGAAGAAGCGGAAGCGAGAG 235 GAAGAAGCGGAAGCGAGAGA236 CCGCCCAGGAAGAGAAGAAG 237 AGAGAGGGAGCACTGTGACA 238AGGGAGCACTGTGACACGGA 239 GAGGGAGCACTGTGACACGG 240 GCACTGTGACACGGAGGGAG241 GAGGCTGACGACTTTGATCC 242 AGGCTGACGACTTTGATCCT 243TCCACCTCCACCTTCTTCCC 244 CGACTTTGATCCTGGGAAGA 245 CTTTGATCCTGGGAAGAAGG246 TGATCCTGGGAAGAAGGTGG 247 TCCTGGGAAGAAGGTGGAGG 248CGGACTGGCCGATCTGGGGG 249 ACGCTCGGACTGGCCGATCT 250 AGGTGGAGCCGCCCCCAGAT251 CGCTCGGACTGGCCGATCTG 252 GCTCGGACTGGCCGATCTGG 253CACGCTCGGACTGGCCGATC 254 TGTGTCCGGCACGCTCGGAC 255 CTGGCTGTGTCCGGCACGCT256 ATCGGCCAGTCCGAGCGTGC 257 CACCCTTGCCTGGCTGTGTC 258CGAGCGTGCCGGACACAGCC 259 TGTTCCAGGAGTTGCTGAAT 260 CACACCTATTCAGCAACTCC261 GCTGGCGGAGGAAGTGTTCC 262 TTTACCTCTGAAGCTGGCGG 263CCCCGGTTTACCTCTGAAGC 264 ACTTCCTCCGCCAGCTTCAG 265 CAGGAAAAGCAAAAAATCCA266 GCTTTCAGAAAAGATCCCCA 267 AGGAAAAGCAAAAAATCCAT 268GGAAAAGCAAAAAATCCATG 269 GGAGCAATTGCATCCGTGAC 270 GTCACGGATGCAATTGCTCC271 TTTATTATCATTGAATATCC 272 AATGATAATAAAACATCCCA 273ATAAAACATCCCATGGATTT 274 TTCATGGTGCCAAAATCCAT 275 TTTCATGGTGCCAAAATCCA276 TAATGAATACAAGTCAGTTA 277 CAAGTCAGTTACGGAATTTA 278ATAATGCAATGACATACAAT 279 AACTTGTAGTACACGGTATC 280 CTTCGCCAACTTGTAGTACA281 AGATACCGTGTACTACAAGT 282 GCGAAGAAGATCCTTCACGC 283TCATCTTAAAGCCTGCGTGA 284 TTCTCAGCAGGCAGCTCTTT 285 CAATGAAGATACAGCTGTTG286 ACTGGTACAACTTCAGGGAC 287 CTTGTACTGGTACAACTTCA 288ACTTGTACTGGTACAACTTC 289 TTGGCAGTTTCTACTTGTAC 290 TACCTGATAACTTCTCTACT291 AGCCGAGTAGAGAAGTTATC 292 AGCTGCATGTTTGAGCCTGA 293GCTGCATGTTTGAGCCTGAA 294 AAGCTGCAGGCATTCCCTTC 295 GGTACTGTCCGTCAAGCTGC296 AGGGAATGCCTGCAGCTTGA 297 CTTGACGGACAGTACCGCAG 298CGCCAGCACGTGCTCCTCTG 299 TACCGCAGAGGAGCACGTGC 300 AGAGGAGCACGTGCTGGCGC301 GGAGCACGTGCTGGCGCTGG 302 AGCACGCAGCTGACGAAGCT 303GCACGCAGCTGACGAAGCTC 304 CAGCTGACGAAGCTCGGGAC 305 AAGCTCGGGACAGGATCAAC306 CCTTGCCGCCTGGGAGGAAC 307 AGGATCAACCGGTTCCTCCC 308ATCAACCGGTTCCTCCCAGG 309 GCACTACCTTGCCGCCTGGG 310 AGAGCACTACCTTGCCGCCT311 CCGGTTCCTCCCAGGCGGCA 312 TCCTCTTCAGATAGCCCATC 313ATGGGCTATCTGAAGAGGAA 314 GGGCTATCTGAAGAGGAACG 315 TGGGCTATCTGAAGAGGAAC316 TATCTGAAGAGGAACGGGGA 317 ATCTGAAGAGGAACGGGGAC 318TGTTGACCACGCTGTAGAGC 319 GCTCTACAGCGTGGTCAACA 320 CGGGAGCCTGCTCTACAGCG321 CGTGGTCAACACGGCCGAGC 322 CCCACCATCAGCGTCCGGCT 323ACGGCCGAGCCGGACGCTGA 324 GGGCACCCACCATCAGCGTC 325 GCCGAGCCGGACGCTGATGG326 CCATGTCCGTGTTGCAGAGG 327 CCGAGCCGGACGCTGATGGT 328CGAGCTCAAGTCCACCGGGT 329 GCGAGCTCAAGTCCACCGGG 330 AGAGCGAGCTCAAGTCCACC331 GAGAGCGAGCTCAAGTCCAC 332 GAAGCCTGGGAGTAGCTTAC 333CTCTCCAGTAAGCTACTCCC 334 AGCCCAGCGTGGTGAAGCCT 335 AAGCCCAGCGTGGTGAAGCC336 ACTCCCAGGCTTCACCACGC 337 CTCCCAGGCTTCACCACGCT 338CTCGTCTTTGAAGCCCAGCG 339 CACTGGAGAGAAAGGTGACT 340 GCACTGGAGAGAAAGGTGAC341 AGTAGTGGCACTGGAGAGAA 342 CGAAAGCGCAGTAGTGGCAC 343CTGCATCGAAAGCGCAGTAG 344 ATGCAGAATAATTCAGTATT 345 AGTATTTGGCGACTTGAAGT346 CGACTTGAAGTCGGACGAGA 347 GAGCTGCTCTACTCAGCCTA 348CACGCCTGTCTCATCTCCGT 349 TCAGCCTACGGAGATGAGAC 350 CAGGCGTGCAGTGTGCGCTG351 CCGCGGCCCCTCTAGCCTGC 352 CATCCTTCACAAACTCCTGC 353TAGCCTGCAGGAGTTTGTGA 354 CAGGAGTTTGTGAAGGATGC 355 AGGAGTTTGTGAAGGATGCT356 TGGGAGCTACAGCAAGAAAG 357 GAGCTACAGCAAGAAAGTGG 358GAAAGTGGTGGACGACCTCC 359 CGCCTGTGATCTGGTCCAGG 360 CTCCGCCTGTGATCTGGTCC361 GACCTCCTGGACCAGATCAC 362 CTCCTGGACCAGATCACAGG 363GCTGGAAGAGCGTCCTAGAG 364 TGCAGCCCACCTGCTTCAGC 365 GACGCTCTTCCAGCTGAAGC366 CTCTTCCAGCTGAAGCAGGT 367 GCTCTTCCAGCTGAAGCAGG 368CCTCCAGATGAAGCCAAGGT 369 GCTTCATCTGGAGGCTTCAT 370 GGCTTCATCTGGAGGCTTCA371 CTTACCTTGGCTTCATCTGG 372 AAACTTACCTTGGCTTCATC 373GAAGCCTCCAGATGAAGCCA 374 TCCTAGGGTGTCCCCAACCT 375 CCTAGGGTGTCCCCAACCTG376 GTGTCTGTCTCCACAGGTTG 377 TGTGTCTGTCTCCACAGGTT 378CCACAGGTTGGGGACACCCT 379 AGAGCTGCTGCTGTCTCCTA 380 CAGAGCTGCTGCTGTCTCCT381 AGACAGCAGCAGCTCTGTTC 382 ATCCACAGAAACGTCGGGAT 383GAGATATCCACAGAAACGTC 384 GGAGATATCCACAGAAACGT 385 GTCCTATCCCGACGTTTCTG386 TCTCCATGCTCAGCTCTCTG 387 CTCACCCAGAGAGCTGAGCA 388ATCTCCATGCTCAGCTCTCT 389 TATCTCCATGCTCAGCTCTC 390 ATGTCCTGTTTACACAGGGA391 TTACACAGGGAAGGTGAAGA 392 AGTTCAAATGGCTGTCGTCA 393TGACGACAGCCATTTGAACT 394 AAGTTCAAATGGCTGTCGTC 395 TCGTCTCATCCAAGTTCAAA396 TGAGACGACGAAGCTCCTGC 397 GTGCTTCGTGCAGGTCCTGC 398GCAGGACCTGCACGAAGCAC 399 GCTCCGCCTGTGCTTCGTGC 400 GGACCTGCACGAAGCACAGG401 CACGAAGCACAGGCGGAGCG 402 AGGCGGAGCGCGGCGGCTCT 403AGGGAGCTGAGGTTGGACGA 404 GTTGGACAGGGAGCTGAGGT 405 AGGCGTTGGACAGGGAGCTG406 CCCTCTCGGAGGCGTTGGAC 407 CCTCTCGGAGGCGTTGGACA 408CTGGTCCCTCTCGGAGGCGT 409 CCCTGTCCAACGCCTCCGAG 410 CCTGTCCAACGCCTCCGAGA411 GTGGTGCTGGTCCCTCTCGG 412 CAGGTGGTGCTGGTCCCTCT 413GCATCTCACCCAGGTGGTGC 414 CGAGAGGGACCAGCACCACC 415 GAGAGGGACCAGCACCACCT416 GTGGGGGCATCTCACCCAGG 417 CCCCGACACTCAGGCGAGAA 418TCCCCGACACTCAGGCGAGA 419 AGCCCTTCTCGCCTGAGTGT 420 CTGGCTGCTCCCCGACACTC421 CCCTTCTCGCCTGAGTGTCG 422 GCCCTTCTCGCCTGAGTGTC 423TAGGGGTCGTGGGTGACGTC 424 AAGAAACTCATAGGGGTCGT 425 GAAGAAACTCATAGGGGTCG426 GAGACTGAAGAAACTCATAG 427 GGAGACTGAAGAAACTCATA 428TGGAGACTGAAGAAACTCAT 429 TCTTCAGTCTCCAGAGCCTG 430 TTGGCAGAGGCCGCAGGCTC431 TAGGTCTTGGCAGAGGCCGC 432 CTAGAGTTAGGTCTTGGCAG 433GGTGGTCTAGAGTTAGGTCT

TABLE 3 Control sgRNA Library SEQ ID NO. gRNA Label GeneNucleic Acid Sequence 434 1|sg_Non_Targeting_Human_ Non_Targeting_HumanGTAGCGAACGTGTCCGGCGT 0001|Non_Targeting_Human 4351|sg_Non_Targeting_Human_ Non_Targeting_Human GACCGGAACGATCTCGCGTA0002|Non_Targeting_Human 436 1|sg_Non_Targeting_Human_Non_Targeting_Human GGCAGTCGTTCGGTTGATAT 0003|Non_Targeting_Human 4371|sg_Non Targeting_Human_ Non_Targeting_Human GCTTGAGCACATACGCGAAT0004|Non_Targeting_Human 438 1|sg_Non_Targeting_Human_Non_Targeting_Human GTGGTAGAATAACGTATTAC 0005|Non_Targeting_Human 4391|sg_Non_Targeting_Human_ Non_Targeting_Human GTCATACATGGATAAGGCTA0006|Non_Targeting Human 440 1|sg_Non_Targeting_Human_Non_Targeting_Human GATACACGAAGCATCACTAG 0007|Non_Targeting_Human 4411|sg_Non_Targeting_Human_ Non_Targeting_Human GAACGTTGGCACTACTTCAC0008|Non_Targeting_Human 442 1|sg_Non_Targeting_Human_Non_Targeting_Human GATCCATGTAATGCGTTCGA 0009|Non_Targeting_Human 4431|sg_Non_Targeting_Human_ Non_Targeting_Human GTCGTGAAGTGCATTCGATC0010|Non_Targeting_Human 444 1|sg_Non_Targeting_Human_Non_Targeting_Human GTTCGACTCGCGTGACCGTA 0011|Non_Targeting_Human 4451|sg_Non_Targeting_Human_ Non_Targeting_Human GAATCTACCGCAGCGGTTCG0012|Non_Targeting_Human 446 1|sg_Non_Targeting_Human_Non_Targeting_Human GAAGTGACGTCGATTCGATA 0013|Non_Targeting_Human 4471|sg_Non_Targeting_Human_ Non_Targeting_Human GCGGTGTATGACAACCGCCG0014|Non_Targeting_Human 448 1|sg_Non_Targeting_Human_Non_Targeting_Human GTACCGCGCCTGAAGTTCGC 0015|Non_Targeting_Human 4491|sg_Non_Targeting_Human_ Non_Targeting_Human GCAGCTCGTGTGTCGTACTC0016|Non_Targeting_Human 450 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGCCTTAAGAGTACTCATC 0017|Non_Targeting_Human 4511|sg_Non_Targeting_Human_ Non_Targeting_Human GAGTGTCGTCGTTGCTCCTA0018|Non_Targeting_Human 452 1|sg_Non_Targeting_Human_Non_Targeting_Human GCAGCTCGACCTCAAGCCGT 0019|Non_Targeting_Human 4531|sg_Non_Targeting_Human_ Non_Targeting_Human GTATCCTGACCTACGCGCTG0020|Non_Targeting_Human 454 1|sg_Non_Targeting_Human_Non_Targeting_Human GTGTATCTCAGCACGCTAAC 0021|Non_Targeting_Human 4551|sg_Non_Targeting_Human_ Non_Targeting_Human GTCGTCATACAACGGCAACG0022|Non_Targeting_Human 456 1|sg_Non_Targeting_Human_Non_Targeting_Human GTCGTGCGCTTCCGGCGGTA 0023|Non_Targeting_Human 4571|sg_Non_Targeting_Human_ Non_Targeting_Human GCGGTCCTCAGTAAGCGCGT0024|Non_Targeting_Human 458 1|sg_Non_Targeting_Human_Non_Targeting_Human GCTCTGCTGCGGAAGGATTC 0025|Non_Targeting_Human 4591|sg_Non_Targeting_Human_ Non_Targeting Human GCATGGAGGAGCGTCGCAGA0026|Non_Targeting_Human 460 1|sg_Non_Targeting_Human_Non_Targeting_Human GTAGCGCGCGTAGGAGTGGC 0027|Non_Targeting_Human 4611|sg_Non_Targeting_Human_ Non_Targeting_Human GATCACCTGCATTCGTACAC0028|Non_Targeting_Human 462 1|sg_Non_Targeting_Human_Non_Targeting_Human GCACACCTAGATATCGAATG 0029|Non_Targeting_Human 4631|sg_Non_Targeting_Human_ Non_Targeting_Human GTTGATCAACGCGCTTCGCG0030|Non_Targeting_Human 464 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGTCTCACTCACTCCATCG 0031|Non_Targeting_Human 4651|sg_Non_Targeting_Human_ Non_Targeting_Human GCCGACCAACGTCAGCGGTA0032|Non Targeting_Human 466 1|sg_Non_Targeting_Human_Non_Targeting_Human GGATACGGTGCGTCAATCTA 0033|Non_Targeting_Human 4671|sg_Non_Targeting_Human_ Non_Targeting_Human GAATCCAGTGGCGGCGACAA0034|Non_Targeting_Human 468 1|sg_Non_Targeting_Human_Non Targeting_Human GCACTGTCAGTGCAACGATA 0035|Non_Targeting_Human 4691|sg_Non_Targeting_Human_ Non_Targeting_Human GCGATCCTCAAGTATGCTCA0036|Non_Targeting_Human 470 1|sg_Non_Targeting_Human_Non_Targeting_Human GCTAATATCGACACGGCCGC 0037|Non_Targeting_Human 4711|sg_Non_Targeting_Human_ Non_Targeting_Human GGAGATGCATCGAAGTCGAT0038|Non_Targeting_Human 472 1|sg_Non_Targeting_Human_Non_Targeting_Human GGATGCACTCCATCTCGTCT 0039|Non_Targeting_Human 4731|sg_Non_Targeting_Human_ Non_Targeting_Human GTGCCGAGTAATAACGCGAG0040|Non_Targeting_Human 474 1|sg_Non_Targeting_Human_Non Targeting_Human GAGATTCCGATGTAACGTAC 0041|Non_Targeting_Human 4751|sg_Non_Targeting_Human_ Non_Targeting_Human GTCGTCACGAGCAGGATTGC0042|Non_Targeting_Human 476 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGTTAGTCACTTAGCTCGA 0043|Non-Targeting_Human 4771|sg_Non_Targeting_Human_ Non_Targeting_Human GTTCACACGGTGTCGGATAG0044|Non_Targeting_Human 478 1|sg_Non_Targeting_Human_Non_Targeting_Human GGATAGGTGACCTTAGTACG 0045|Non_Targeting_Human 4791|sg_Non_Targeting_Human_ Non_Targeting_Human GTATGAGTCAAGCTAATGCG0046|Non_Targeting_Human 480 1|sg_Non_Targeting_Human_Non_Targeting_Human GCAACTATTGGAATACGTGA 0047|Non_Targeting_Human 4811|sg_Non_Targeting_Human_ Non_Targeting_Human GTTACCTTCGCTCGTCTATA0048|Non_Targeting_Human 482 1|sg_Non_Targeting_Human_Non_Targeting_Human GTACCGAGCACCACAGGCCG 0049|Non_Targeting_Human 4831|sg_Non_Targeting_Human_ Non_Targeting_Human GTCAGCCATCGGATAGAGAT0050|Non_Targeting_Human 484 1|sg_Non_Targeting_Human_Non_Targeting_Human GTACGGCACTCCTAGCCGCT 0051|Non_Targeting_Human 4851|sg_Non_Targeting_Human_ Non_Targeting_Human GGTCCTGTCGTATGCTTGCA0052|Non_Targeting_Human 486 1|sg_Non_Targeting_Human_Non_Targeting_Human GCCGCAATATATGCGGTAAG 0053|Non_Targeting_Human 4871|sg_Non_Targeting_Human_ Non_Targeting_Human GCGCACGTATAATCCTGCGT0054|Non_Targeting_Human 488 1|sg_Non_Targeting_Human_Non_Targeting_Human GTGCACAACACGATCCACGA 0055|Non_Targeting_Human 4891|sg_Non_Targeting_Human_ Non_Targeting_Human GCACAATGTTGACGTAAGTG0056|Non_Targeting_Human 490 1|sg_Non_Targeting_Human_Non_Targeting_Human GTAAGATGCTGCTCACCGTG 0057|Non_Targeting_Human 4911|sg_Non_Targeting_Human_ Non_Targeting_Human GTCGGTGATCCAACGTATCG0058|Non_Targeting_Human 492 1|sg_Non_Targeting_Human_Non_Targeting_Human GAGCTAGTAGGACGCAAGAC 0059|Non_Targeting_Human 4931|sg_Non_Targeting_Human_ Non_Targeting_Human GTACGTGGAAGCTTGTGGCC0060|Non_Targeting_Human 494 1|sg_Non_Targeting_Human_Non_Targeting_Human GAGAACTGCCAGTTCTCGAT 0061|Non_Targeting_Human 4951|sg_Non_Targeting_Human_ Non Targeting_Human GCCATTCGGCGCGGCACTTC0062|Non_Targeting_Human 496 1|sg_Non_Targeting_Human_Non_Targeting_Human GCACACGACCAATCCGCTTC 0063|Non_Targeting_Human 4971|sg_Non_Targeting_Human_ Non_Targeting_Human GAGGTGATCGATTAAGTACA0064|Non_Targeting_Human 498 1|sg_Non_Targeting_Human_Non_Targeting_Human GTCACTCGCAGACGCCTAAC 0065|Non_Targeting_Human 4991|sg_Non_Targeting_Human_ Non_Targeting_Human GCGCTACGGAATCATACGTT0066|Non_Targeting_Human 500 1|sg_Non_Targeting_Human_Non_Targeting_Human GGTAGGACCTCACGGCGCGC 0067|Non_Targeting_Human 5011|sg_Non_Targeting_Human_ Non_Targeting_Human GAACTGCATCTTGTTGTAGT0068|Non_Targeting_Human 502 1|sg_Non_Targeting_Human_Non_Targeting_Human GATCCTGATCCGGCGGCGCG 0069|Non_Targeting_Human 5031|sg_Non_Targeting_Human_ Non_Targeting_Human GGTATGCGCGATCCTGAGTT0070|Non_Targeting_Human 504 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGGAGCTAGAGAGCGGTCA 0071|Non_Targeting_Human 5051|sg_Non_Targeting_Human_ Non_Targeting_Human GAATGGCAATTACGGCTGAT0072|Non_Targeting_Human 506 1|sg_Non_Targeting_Human_Non_Targeting_Human GTATGGTGAGTAGTCGCTTG 0073|Non_Targeting_Human 5071|sg_Non_Targeting_Human_ Non_Targeting_Human GTGTAATTGCGTCTAGTCGG0074|Non_Targeting_Human 508 1|sg_Non_Targeting_Human_Non_Targeting_Human GGTCCTGGCGAGGAGCCTTG 0075|Non_Targeting_Human 5091|sg_Non_Targeting_Human_ Non_Targeting_Human GAAGATAAGTCGCTGTCTCG0076|Non_Targeting_Human 510 1|sg_Non_Targeting_Human_Non_Targeting_Human GTCGGCGTTCTGTTGTGACT 0077|Non_Targeting_Human 5111|sg_Non_Targeting_Human_ Non_Targeting_Human GAGGCAAGCCGTTAGGTGTA0078|Non_Targeting_Human 512 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGGATCCAGATCTCATTCG 0079|Non_Targeting_Human 5131|sg_Non_Targeting_Human_ Non_Targeting_Human GGAACATAGGAGCACGTAGT0080|Non_Targeting_Human 514 1|sg_Non_Targeting_Human_Non_Targeting_Human GTCATCATTATGGCGTAAGG 0081|Non_Targeting_Human 5151|sg_Non_Targeting_Human_ Non_Targeting_Human GCGACTAGCGCCATGAGCGG0082|Non_Targeting_Human 516 1|sg_Non_Targeting_Human_Non_Targeting_Human GGCGAAGTTCGACATGACAC 0083|Non_Targeting_Human 5171|sg_Non_Targeting_Human_ Non_Targeting_Human GCTGTCGTGTGGAGGCTATG0084|Non_Targeting_Human 518 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGGAGAGCATTGACCTCAT 0085|Non_Targeting_Human 5191|sg_Non_Targeting_Human_ Non_Targeting_Human GACTAATGGACCAAGTCAGT0086|Non_Targeting_Human 520 1|sg_Non_Targeting Human_Non_Targeting_Human GCGGATTAGAGGTAATGCGG 0087|Non_Targeting_Human 5211|sg_Non_Targeting_Human_ Non_Targeting_Human GCCGACGGCAATCAGTACGC0088|Non_Targeting_Human 522 1|sg_Non_Targeting_Human_Non_Targeting_Human GTAACCTCTCGAGCGATAGA 0089|Non_Targeting_Human 5231|sg_Non_Targeting_Human_ Non_Targeting_Human GACTTGTATGTGGCTTACGG0090|Non_Targeting_Human 524 1|sg_Non_Targeting_Human_Non_Targeting_Human GTCACTGTGGTCGAACATGT 0091|Non_Targeting_Human 5251|sg_Non_Targeting_Human_ Non_Targeting_Human GTACTCCAATCCGCGATGAC0092|Non_Targeting_Human 526 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGTTGGCACGATGTTACGG 0093|Non_Targeting_Human 5271|sg_Non_Targeting_Human_ Non_Targeting_Human GAACCAGCCGGCTAGTATGA0094|Non_Targeting_Human 528 1|sg_Non_Targeting_Human_Non_Targeting_Human GTATACTAGCTAACCACACG 0095|Non_Targeting_Human 5291|sg_Non_Targeting_Human_ Non_Targeting_Human GAATCGGAATAGTTGATTCG0096|Non_Targeting_Human 530 1|sg_Non_Targeting Human_Non_Targeting_Human GAGCACTTGCATGAGGCGGT 0097|Non Targeting Human 5311|sg_Non_Targeting_Human_ Non_Targeting_Human GAACGGCGATGAAGCCAGCC0098|Non_Targeting_Human 532 1|sg_Non_Targeting_Human_Non_Targeting_Human GCAACCGAGATGAGAGGTTC 0099|Non Targeting_Human 5331|sg_Non_Targeting_Human_ Non_Targeting_Human GCAAGATCAATATGCGTGAT0100|Non_Targeting_Human 534 1|sg_Non_Targeting_Human_Non_Targeting_Human ACGGAGGCTAAGCGTCGCAA GA_0101|Non_Targeting_Human 5351|sg_Non_Targeting_Human_ Non_Targeting_Human CGCTTCCGCGGCCCGTTCAAGA_0102|Non_Targeting_Human 536 1|sg_Non_Targeting_Human_Non_Targeting_Human ATCGTTTCCGCTTAACGGCG GA_0103|Non_Targeting_Human 5371|sg_Non_Targeting_Human_ Non_Targeting_Human GTAGGCGCGCCGCTCTCTACGA_0104|Non_Targeting_Human 538 1|sg_Non_Targeting_Human_Non Targeting_Human CCATATCGGGGCGAGACATG GA_0105|Non_Targeting_Human 5391|sg_Non_Targeting_Human_ Non_Targeting_Human TACTAACGCCGCTCCTACAGGA_0106|Non_Targeting_Human 540 1|sg_Non_Targeting_Human_Non_Targeting_Human TGAGGATCATGTCGAGCGCC GA_0107|Non_Targeting_Human 5411|sg_Non_Targeting_Human_ Non_Targeting_Human GGGCCCGCATAGGATATCGCGA_0108|Non_Targeting_Human 542 1|sg_Non_Targeting_Human_Non_Targeting_Human TAGACAACCGCGGAGAATGC GA_0109|Non_Targeting_Human 5431|sg_Non_Targeting_Human_ Non_Targeting_Human ACGGGCGGCTATCGCTGACTGA_0110|Non_Targeting_Human 544 1|sg_Non_Targeting_Human_Non_Targeting_Human CGCGGAAATTTTACCGACGA GA_0111|Non_Targeting_Human 5451|sg_Non_Targeting_Human_ Non_Targeting_Human CTTACAATCGTCGGTCCAATGA_0112|Non_Targeting_Human 546 1|sg_Non_Targeting_Human_Non_Targeting_Human GCGTGCGTCCCGGGTTACCC GA_0113|Non_Targeting_Human 5471|sg_Non_Targeting_Human_ Non_Targeting_Human CGGAGTAACAAGCGGACGGAGA_0114|Non_Targeting_Human 548 1|sg_Non_Targeting_Human_Non_Targeting_Human CGAGTGTTATACGCACCGTT GA_0115|Non_Targeting_Human 5491|sg_Non_Targeting_Human_ Non_Targeting_Human CGACTAACCGGAAACTTTTTGA_0116|Non_Targeting_Human 550 1|sg_Non_Targeting_Human_Non_Targeting_Human CAACGGGTTCTCCCGGCTAC GA_0117|Non_Targeting_Human 5511|sg_Non_Targeting_Human_ Non_Targeting_Human CAGGAGTCGCCGATACGCGTGA_0118|Non_Targeting_Human 552 1|sg_Non_Targeting_Human_Non_Targeting_Human TTCACGTCGTCTCGCGACCA GA_0119|Non_Targeting_Human 5531|sg_Non_Targeting_Human_ Non Targeting_Human GTGTCGGATTCCGCCGCTTAGA_0120|Non_Targeting_Human 554 1|sg_Non_Targeting_Human_Non_Targeting_Human CACGAACTCACACCGCGCGA GA_0121|Non_Targeting_Human 5551|sg_Non_Targeting_Human_ Non_Targeting_Human CGCTAGTACGCTCCTCTATAGA_0122|Non_Targeting_Human 556 1|sg_Non_Targeting_Human_Non_Targeting_Human TCGCGCTTGGGTTATACGCT GA_0123|Non_Targeting_Human 5571|sg_Non_Targeting_Human_ Non_Targeting_Human CTATCTCGAGTGGTAATGCGGA_0124|Non_Targeting_Human 558 1|sg_Non_Targeting_Human_Non_Targeting_Human AATCGACTCGAACTTCGTGT GA_0125|Non_Targeting_Human 5591|sg_Non_Targeting_Human_ Non_Targeting_Human CCCGATGGACTATACCGAACGA_0126|Non_Targeting_Human 560 1|sg_Non_Targeting_Human_Non_Targeting_Human ACGTTCGAGTACGACCAGCT GA_0127|Non_Targeting Human 5611|sg_Non_Targeting_Human_ Non Targeting_Human CGCGACGACTCAACCTAGTCGA_0128|Non_Targeting_Human 562 1|sg_Non_Targeting_Human_Non_Targeting_Human GGTCACCGATCGAGAGCTAG GA_0129|Non_Targeting_Human 5631|sg_Non_Targeting_Human_ Non_Targeting_Human CTCAACCGACCGTATGGTCAGA_0130|Non_Targeting_Human 564 1|sg_Non_Targeting_Human_Non Targeting_Human CGTATTCGACTCTCAACGCG GA_0131|Non_Targeting_Human 5651|sg_Non_Targeting_Human_ Non Targeting_Human CTAGCCGCCCAGATCGAGCCGA_0132|Non_Targeting_Human 566 1|sg_Non_Targeting_Human_Non_Targeting_Human GAATCGACCGACACTAATGT GA_0133|Non_Targeting_Human 5671|sg_Non_Targeting_Human_ Non_Targeting_Human ACTTCAGTTCGGCGTAGTCAGA_0134|Non_Targeting_Human 568 1|sg_Non_Targeting_Human_Non_Targeting_Human GTGCGATGTCGCTTCAACGT GA_0135|Non_Targeting_Human 5691|sg_Non_Targeting_Human_ Non_Targeting_Human CGCCTAATTTCCGGATCAATGA_0136|Non_Targeting_Human 570 1|sg_Non_Targeting_Human_Non_Targeting_Human CGTGGCCGGAACCGTCATAG GA_0137|Non_Targeting_Human 5711|sg_Non_Targeting_Human_ Non_Targeting_Human ACCCTCCGAATCGTAACGGAGA_0138|Non_Targeting_Human 572 1|sg_Non_Targeting_Human_Non_Targeting_Human AAACGGTACGACAGCGTGTG GA_0139|Non_Targeting_Human 5731|sg_Non_Targeting_Human_ Non_Targeting_Human ACATAGTCGACGGCTCGATTGA_0140|Non_Targeting_Human 574 1|sg_Non_Targeting_Human_Non_Targeting_Human GATGGCGCTTCAGTCGTCGG GA_0141|Non_Targeting_Human 5751|sg_Non_Targeting_Human_ Non_Targeting_Human ATAATCCGGAAACGCTCGACGA_0142|Non_Targeting_Human 576 1|sg_Non_Targeting_Human_Non_Targeting_Human CGCCGGGCTGACAATTAACG GA_0143|Non_Targeting_Human 5771|sg_Non_Targeting_Human_ Non_Targeting_Human CGTCGCCATATGCCGGTGGCGA_0144|Non_Targeting_Human 578 1|sg_Non_Targeting_Human_Non_Targeting_Human CGGGCCTATAACACCATCGA GA_0145|Non_Targeting_Human 5791|sg_Non_Targeting_Human_ Non_Targeting_Human CGCCGTTCCGAGATACTTGAGA_0146|Non_Targeting_Human 580 1|sg_Non_Targeting_Human_Non_Targeting_Human CGGGACGTCGCGAAAATGTA GA_0147|Non_Targeting_Human 5811|sg_Non_Targeting_Human_ Non_Targeting_Human TCGGCATACGGGACACACGCGA_0148|Non_Targeting_Human 582 1|sg_Non_Targeting_Human_Non_Targeting_Human AGCTCCATCGCCGCGATAAT GA_0149|Non_Targeting_Human 5831|sg_Non_Targeting_Human_ Non_Targeting_Human ATCGTATCATCAGCTAGCGCGA_0150|Non_Targeting_Human 584 1|sg_Non_Targeting_Human_Non_Targeting_Human TCGATCGAGGTTGCATTCGG GA_0151|Non_Targeting_Human 5851|sg_Non_Targeting_Human_ Non_Targeting_Human CTCGACAGTTCGTCCCGAGCGA_0152|Non_Targeting_Human 586 1|sg_Non_Targeting_Human_Non_Targeting_Human CGGTAGTATTAATCGCTGAC GA_0153|Non_Targeting_Human 5871|sg_Non_Targeting_Human_ Non_Targeting_Human TGAACGCGTGTTTCCTTGCAGA_0154|Non_Targeting_Human 588 1|sg_Non_Targeting_Human_Non_Targeting_Human CGACGCTAGGTAACGTAGAG GA_0155|Non_Targeting_Human 5891|sg_Non_Targeting_Human_ Non_Targeting_Human CATTGTTGAGCGGGCGCGCTGA_0156|Non_Targeting_Human 590 1|sg_Non_Targeting_Human_Non_Targeting_Human CCGCTATTGAAACCGCCCAC GA_0157|Non_Targeting_Human 5911|sg_Non_Targeting_Human_ Non_Targeting_Human AGACACGTCACCGGTCAAAAGA_0158|Non_Targeting_Human 592 1|sg_Non_Targeting_Human_Non_Targeting_Human TTTACGATCTAGCGGCGTAG GA_0159|Non_Targeting_Human 5931|sg_Non_Targeting_Human_ Non_Targeting_Human TTCGCACGATTGCACCTTGGGA_0160|Non_Targeting_Human 594 1|sg_Non_Targeting_Human_Non_Targeting_Human GGTTAGAGACTAGGCGCGCG GA_0161|Non_Targeting_Human 5951|sg_Non_Targeting_Human_ Non_Targeting_Human CCTCCGTGCTAACGCGGACGGA_0162|Non_Targeting_Human 596 1|sg_Non_Targeting_Human_Non_Targeting_Human TTATCGCGTAGTGCTGACGT GA_0163|Non_Targeting_Human 5971|sg_Non_Targeting_Human_ Non_Targeting_Human TACGCTTGCGTTTAGCGTCCGA_0164|Non_Targeting_Human 598 1|sg_Non_Targeting_Human_Non_Targeting_Human CGCGGCCCACGCGTCATCGC GA_0165|Non_Targeting_Human 5991|sg_Non_Targeting_Human_ Non_Targeting_Human AGCTCGCCATGTCGGTTCTCGA_0166|Non_Targeting_Human 600 1|sg_Non_Targeting_Human_Non_Targeting_Human AACTAGCCCGAGCAGCTTCG GA_0167|Non_Targeting_Human 6011|sg_Non_Targeting_Human_ Non_Targeting_Human CGCAAGGTGTCGGTAACCCTGA_0168|Non_Targeting_Human 602 1|sg_Non_Targeting_Human_Non_Targeting_Human CTTCGACGCCATCGTGCTCA GA_0169|Non_Targeting_Human 6031|sg_Non_Targeting_Human_ Non_Targeting_Human TCCTGGATACCGCGTGGTTAGA_0170|Non_Targeting_Human 604 1|sg_Non_Targeting_Human_Non_Targeting_Human ATAGCCGCCGCTCATTACTT GA_0171|Non_Targeting_Human 6051|sg_Non_Targeting_Human_ Non_Targeting_Human GTCGTCCGGGATTACAAAATGA_0172|Non_Targeting_Human 606 1|sg_Non_Targeting_Human_Non_Targeting_Human TAATGCTGCACACGCCGAAT GA_0173|Non_Targeting_Human 6071|sg_Non_Targeting_Human_ Non_Targeting_Human TATCGCTTCCGATTAGTCCGGA_0174|Non_Targeting_Human 608 1|sg_Non_Targeting_Human_Non_Targeting_Human GTACCATACCGCGTACCCTT GA_0175|Non_Targeting_Human 6091|sg_Non_Targeting_Human_ Non_Targeting_Human TAAGATCCGCGGGTGGCAACGA_0176|Non_Targeting_Human 610 1|sg_Non_Targeting_Human_Non_Targeting_Human GTAGACGTCGTGAGCTTCAC GA_0177|Non_Targeting_Human 6111|sg_Non_Targeting_Human_ Non_Targeting_Human TCGCGGACATAGGGCTCTAAGA_0178|Non_Targeting_Human 612 1|sg_Non_Targeting_Human_Non_Targeting_Human AGCGCAGATAGCGCGTATCA GA_0179|Non_Targeting_Human 6131|sg_Non_Targeting_Human_ Non_Targeting_Human GTTCGCTTCGTAACGAGGAAGA_0180|Non_Targeting_Human 614 1|sg_Non_Targeting_Human_Non_Targeting_Human GACCCCCGATAACTTTTGAC GA_0181|Non_Targeting_Human 6151|sg_Non_Targeting_Human_ Non_Targeting_Human ACGTCCATACTGTCGGCTACGA_0182|Non_Targeting_Human 616 1|sg_Non_Targeting_Human_Non_Targeting_Human GTACCATTGCCGGCTCCCTA GA_0183|Non_Targeting_Human 6171|sg_Non_Targeting_Human_ Non_Targeting_Human TGGTTCCGTAGGTCGGTATAGA_0184|Non_Targeting_Human 618 1|sg_Non_Targeting_Human_Non_Targeting_Human TCTGGCTTGACACGACCGTT GA_0185|Non_Targeting_Human 6191|sg_Non_Targeting_Human_ Non Targeting_Human CGCTAGGTCCGGTAAGTGCGGA_0186|Non_Targeting_Human 620 1|sg_Non_Targeting_Human_Non_Targeting_Human AGCACGTAATGTCCGTGGAT GA_0187|Non_Targeting_Human 6211|sg_Non_Targeting_Human_ Non_Targeting_Human AAGGCGCGCGAATGTGGCAGGA_0188|Non_Targeting_Human 622 1|sg_Non_Targeting_Human_Non_Targeting_Human ACTGCGGAGCGCCCAATATC GA_0189|Non_Targeting_Human 6231|sg_Non_Targeting_Human_ Non_Targeting_Human CGTCGAGTGCTCGAACTCCAGA_0190|Non_Targeting_Human 624 1|sg_Non_Targeting_Human_Non_Targeting_Human TCGCAGCGGCGTGGGATCGG GA_0191|Non_Targeting_Human 6251|sg_Non_Targeting_Human_ Non_Targeting_Human ATCTGTCCTAATTCGGATCGGA_0192|Non_Targeting_Human 626 1|sg_Non_Targeting_Human_Non_Targeting_Human TGCGGCGTAATGCTTGAAAG GA_0193|Non_Targeting_Human 6271|sg_Non_Targeting_Human_ Non_Targeting_Human CGAACTTAATCCCGTGGCAAGA_0194|Non_Targeting_Human 628 1|sg_Non_Targeting_Human_Non_Targeting_Human GCCGTGTTGCTGGATACGCC GA_0195|Non_Targeting_Human 6291|sg_Non_Targeting_Human_ Non_Targeting_Human TACCCTCCGGATACGGACTGGA_0196|Non_Targeting_Human 630 1|sg_Non_Targeting_Human_Non_Targeting_Human CCGTTGGACTATGGCGGGTC GA_0197|Non_Targeting_Human 6311|sg_Non_Targeting_Human_ Non_Targeting_Human GTACGGGGCGATCATCCACAGA_0198|Non_Targeting_Human 632 1|sg_Non_Targeting_Human_Non Targeting Human AAGAGTAGTAGACGCCCGGG GA_0199|Non_Targeting_Human 6331|sg_Non_Targeting_Human_ Non_Targeting_Human AAGAGCGAATCGATTTCGTGGA_0200|Non_Targeting_Human 634 3|sg_hCDC16_CC_1|CDC16 CDC16TCAACACCAGTGCCTGACGG 635 3|sg_hCDC16_CC_2|CDC16 CDC16AAAGTAGCTTCACTCTCTCG 636 3|sg_hCDC16_CC_3|CDC16 CDC16GAGCCAACCAATAGATGTCC 637 3|sg_hCDC16_CC_4|CDC16 CDC16GCGCCGCCATGAACCTAGAG 638 3|sg_hGTF2B_CC_1|GTF2B GTF2BACAAAGGTTGGAACAGAACC 639 3|sg_hGTF2B_CC_2|GTF2B GTF2BGGTGACCGGGTTATTGATGT 640 3|sg_hGTF2B_CC 3|GTF2B GTF2BTTAGTGGAGGACTACAGAGC 641 3|sg_hGTF2B_CC_4|GTF2B GTF2BACATATAGCCCGTAAAGCTG 642 3|sg_hHSPA5_CC_1|HSPA5 HSPA5CGTTGGCGATGATCTCCACG 643 3|sg_hHSPA5_CC_2|HSPA5 HSPA5TGGCCTTTTCTACCTCGCGC 644 3|sg_hHSPA5_CC_3|HSPA5 HSPA5AATGGAGATACTCATCTGGG 645 3|sg_hHSPA5_CC_4|HSPA5 HSPA5GAAGCCCGTCCAGAAAGTGT 646 3|sg_hHSPA9_CC_1|HSPA9 HSPA9CAATCTGAGGAACTCCACGA 647 3|sg_hHSPA9_CC_2|HSPA9 HSPA9AGGCTGCGGCGCCCACGAGA 648 3|sg_hHSPA9_CC_3|HSPA9 HSPA9ACTTTGACCAGGCCTTGCTA 649 3|sg_hHSPA9_CC_4|HSPA9 HSPA9ACCTTCCATAACTGCCACGC 650 3|sg_hPAFAH1B1_CC_1|PAFA PAFAH1B1CGAGGCGTACATACCCAAGG H1B1 651 3|sg_hPAFAH1B1_CC_2|PAFA PAFAH1B1ATGGTACGGCCAAATCAAGA H1B1 652 3|sg_hPAFAH1B1_CC_3|PAFA PAFAH1B1TCTTGTAATCCCATACGCGT H1B1 653 3|sg_hPAFAH1B1_CC_4|PAFA PAFAH1B1ATTCACAGGACACAGAGAAT H1B1 654 3|sg_hPCNA_CC_1|PCNA PCNACCAGGGCTCCATCCTCAAGA 655 3|sg_hPCNA_CC_2|PCNA PCNA TGAGCTGCACCAAAGAGACG656 3|sg_hPCNA_CC_3|PCNA PCNA ATGTCTGCAGATGTACCCCT 6573|sg_hPCNA_CC_4|PCNA PCNA CGAAGATAACGCGGATACCT 6583|sg_hPOLR2L_CC_1|POLR2L POLR2L GCTGCAGGCCGAGTACACCG 6593|sg_hPOLR2L_CC_2|POLR2L POLR2L ACAAGTGGGAGGCTTACCTG 6603|sg_hPOLR2L_CC_3|POLR2L POLR2L GCAGCGTACAGGGATGATCA 6613|sg_hPOLR2L_CC_4|POLR2L POLR2L GCAGTAGCGCTTCAGGCCCA 6623|sg_hRPL9_CC_1|RPL9 RPL9 CAAATGGTGGGGTAACAGAA 663 3|sg_hRPL9_CC_2|RPL9RPL9 GAAAGGAACTGGCTACCGTT 664 3|sg_hRPL9_CC_3|RPL9 RPL9AGGGCTTCCGTTACAAGATG 665 3|sg_hRPL9_CC_4|RPL9 RPL9 GAACAAGCAACACCTAAAAG666 3|sg_hSF3A3_CC_1|SF3A3 SF3A3 TGAGGAGAAGGAACGGCTCA 6673|sg_hSF3A3_CC_2|SF3A3 SF3A3 GGAAGAATGCAGAGTATAAG 6683|sg_hSF3A3_CC_3|SF3A3 SF3A3 GGAATTTGAGGAACTCCTGA 6693|sg_hSF3A3_CC_4|SF3A3 SF3A3 GCTCACCGGCCATCCAGGAA 6703|sg_hSF3B3_CC_1|SF3B3 SF3B3 ACTGGCCAGGAACGATGCGA 6713|sg_hSF3B3_CC_2|SF3B3 SF3B3 GCAGCTCCAAGATCTTCCCA 6723|sg_hSF3B3_CC_3|SF3B3 SF3B3 GAATGAGTACACAGAACGGA 6733|sg_hSF3B3_CC_4|SF3B3 SF3B3 GGAGCAGGACAAGGTCGGGG

Example 2—BRD9 Degrader Depletes BRD9 Protein

The following example demonstrates the depletion of the BRD9 protein insynovial sarcoma cells treated with a BRD9 degrader.

Procedure:

Cells were treated with DMSO or the BRD9 degrader, Compound 1 (alsoknown as dBRD9, see Remillard et al, Angew. Chem. Int. Ed. Engl.56(21):5738-5743 (2017); see structure of Compound 1 below), forindicated doses and timepoints.

Whole cell extracts were fractionated by SDS-PAGE and transferred to apolyvinylidene difluoride membrane using a transfer apparatus accordingto the manufacturer's protocols (Bio-Rad). After incubation with 5%nonfat milk in TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween 20) for60 minutes, the membrane was incubated with antibodies against BRD9(1:1,000, Bethyl laboratory A303-781A), GAPDH (1:5,000, Cell SignalingTechnology), and/or MBP (1:1,000, BioRad) overnight at 4° C. Membraneswere washed three times for 10 min and incubated with anti-mouse oranti-rabbit antibodies conjugated with either horseradish peroxidase(HRP, FIGS. 2-3 ) or IRDye (FIG. 4 , 1:20,000, LI-COR) for at least 1 h.Blots were washed with TBST three times and developed with either theECL system according to the manufacturer's protocols (FIGS. 2-3 ) orscanned on an Odyssey CLx Imaging system (FIG. 4 ).

Results:

Treatment of SYO1 synovial sarcoma cells with the BRD9 degrader Compound1 results in dose dependent (FIG. 2 ) and time dependent (FIG. 3 )depletion of BRD9 in the cells. Further, as shown in FIG. 4 , thedepletion of BRD9 by Compound 1 is replicated in a non-synovial sarcomacell line (293T) and may be sustained for at least 5 days.

Example 3—Inhibition of Growth of Synovial Cell Lines by BRD9 Inhibitorsand BRD9 Degraders

The following example demonstrates that BRD9 degraders and inhibitorsselectively inhibit growth of synovial sarcoma cells.

Procedures:

Cells were treated with DMSO or the BRD9 degrader, Compound 1, atindicated concentrations, and proliferation was monitored from day 7 today 14 by measuring confluency over time using an IncuCyte live cellanalysis system (FIG. 5 ). Growth medium and compounds were refreshedevery 3-4 days.

Cells were seeded into 12-well plates and treated with DMSO, 1 μM BRD9inhibitor, Compound 2 (also known as BI-7273, see Martin et al, J MedChem. 59(10):4462-4475 (2016); see structure of Compound 2 below), or 1μM BRD9 degrader, Compound 1.

The number of cells was optimized for each cell line. Growth medium andcompounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T andHS-SY-II cells were fixed and stained at day 11. ASKA cells were fixedand stained at day 23. Staining was done by incubation with crystalviolet solution (0.5 g Crystal Violet, 27 ml 37% Formaldehyde, 100 mL10×PBS, 10 mL Methanol, 863 dH20 to 1 L) for 30 min followed by 3×washes with water and drying the plates for at least 24 h at roomtemperature. Subsequently plates were scanned on an Odyssey CLx Imagingsystem (FIG. 6 ).

Cells were seeded into 96-well ultra low cluster plate (Costar, #7007)in 200 μL complete media and treated at day 2 with DMSO, Staurosporin,or BRD9 degarder, Compound 1, at indicated doses (FIG. 7 ). Media andcompounds were changed every 5 d and cell colonies were imaged at day14.

Results:

As shown in FIGS. 5, 6, and 7 , treatment of synovial sarcoma cell lines(SYO1, Yamato, HS-SY-II, and ASKA) with a BRD9 inhibitor, Compound 2, ora BRD9 degrader, Compound 1, results in inhibition of the growth of thecells, but does not result in inhibition of the growth of non-synovialcontrol cancer cell lines (293T, A549, G401).

Example 4—Selective Inhibition of Growth of Synovial Cell Lines by BRD9Degraders and BRD9 Binders

The following example demonstrates that BRD9 degraders and bindersselectively inhibit growth of synovial sarcoma cells.

Procedure:

Cells were seeded into 6-well or 12-well plates and were treated dailywith a BRD9 degrader (Compound 1), a bromo-domain BRD9 binder (Compound2), E3 ligase binder (lenalidomide), DMSO, or staurosporin (positivecontrol for cell killing), at indicated concentrations. The number ofcells was optimized for each cell line. Growth media was refreshed every5 days. By day 14, medium was removed, cells were washed with PBS, andstained using 500 μL of 0.005% (w/v) crystal violet solution in 25%(v/v) methanol for at least 1 hour at room temperature. Subsequentlyplates were scanned on an Odyssey CLx Imaging system.

Results:

As shown in FIGS. 8 and 9 , treatment of synovial sarcoma cell lines(SYO1, HS-SY-II, and ASKA) with Compound 1 or Compound 2 resulted ininhibition of the growth of the cells, but did not result in inhibitionof the growth of non-synovial control cancer cell lines (RD, HCT116, andCalu6). Overall, Compound 1 showed most significant growth inhibition inall synovial cell lines.

Example 5—Inhibition of Cell Growth in Synovial Sarcoma Cells

The following example shows that BRD9 degraders inhibit cell growth andinduce apoptosis in synovial sarcoma cells.

Procedure:

SYO1 cells were treated for 8 or 13 days with DMSO, a BRD9 degrader(Compound 1) at 200 nM or 1 μM, or an E3 ligase binder (lenalidomide) at200 nM. Compounds were refreshed every 5 days. Cell cycle analysis wasperformed using the Click-iT™ Plus EdU Flow Cytometry Assay(Invitrogen). The apoptosis assay was performed using the Annexin V-FITCApoptosis Detection Kit (Sigma A9210). Assays were performed accordingto the manufacturer's protocol.

Results:

As shown in FIGS. 10-13 , treatment with Compound 1 for 8 or 13 daysresulted in reduced numbers of cells in the S-phase of the cell cycle ascompared to DMSO and lenalidomide.

Treatment with Compound 1 for 8 days also resulted in increased numbersof early- and late-apoptotic cells as compared to DMSO controls.

Example 6—Composition for SS18-SSX1-BAF

The following example shows the identification of BRD9 as a component ofSS18-SSX containing BAF complexes.

Procedure:

A stable 293T cell line expressing HA-SS18SSX1 was generated usinglentiviral integration. SS18-SSX1 containing BAF complexes were subjectto affinity purification and subsequent mass spectrometry analysisrevealed SS18-SSX1 interacting proteins.

Results:

As shown in FIG. 14 , BAF complexes including the SS18-SSX fusionprotein also included BRD9. More than 5 unique peptides were identifiedfor ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69 peptides),SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides),SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22 peptides), DPF1Isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B (6 peptides).

Example 7—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamideformic acid (Compound D1 Formic Acid)

To a stirred mixture of4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dionetrifluoroacetic acid salt (50 mg, 0.097 mmol, 1 equiv) and1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid trifluoroacetic acid salt (50.87 mg, 0.097 mmol, 1 equiv) in DCM (2mL, 31.460 mmol, 323.73 equiv) was added DIEA (37.68 mg, 0.292 mmol, 3equiv) and PyBOP (75.86 mg, 0.146 mmol, 1.5 equiv). The mixture wasstirred for 2 hours at room temperature, and then it was concentratedunder vacuum. The residue was purified by Prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water(0.1% FA) and ACN (25% Phase B up to 45% in 8 minutes); Detector, UV).This resulted in1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamideformic acid (4 mg, 4.81%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.54 (s, 1H), 7.76(s, 1H), 7.62 (d, J=5.8 Hz, 1H), 7.60-7.51 (m, 1H), 7.04 (d, J=7.8 Hz,2H), 6.83 (s, 2H), 5.07 (dd, J=12.5, 5.5 Hz, 1H), 4.31 (s, 2H), 4.05 (s,4H), 3.94 (s, 6H), 3.71 (s, 3H), 3.52-3.45 (s, 2H), 3.22 (t, J=7.0 Hz,2H), 2.91-2.66 (m, 4H), 2.14-2.11 (m, 1H), 1.67 (q, J=7.3 Hz, 2H), 1.54(d, J=7.3 Hz, 2H), 1.45-1.38 (m, 8H). LCMS (ESI) m/z: [M+H]⁺=792.36.

Example 8—Preparation of4-(2-[1-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetyl]-[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(Compound D2)

To a stirred solution of2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)aceticacid (19.99 mg, 0.050 mmol, 1 equiv) and DIPEA (19.50 mg, 0.151 mmol, 3equiv) in DMF (3 mL) was added PyBOP (28.68 mg, 0.075 mmol, 1.5 equiv)and4-(2-[[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dionetrifluoroacetic acid salt (30 mg, 0.050 mmol, 1 equiv). The solution wasstirred for 2 hours at room temperature. The resulting mixture waspurified by Prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN;Flow rate: 25 mL/minute; Gradient: 5% B to 30% B in 8 minutes; 254 nm;R_(t): 7.56 minutes) to afford4-(2-[1-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetyl]-[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(19 mg, 43.83%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.53(d, J=0.8 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (s, 0.3H), 7.76 (s, 2H),7.64 (d, J=5.7 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H),6.80 (s, 2H), 5.14 (t, J=15.7 Hz, 3H), 4.60-4.43 (m, 3H), 4.02 (d,J=13.6 Hz, 4H), 3.91 (s, 6H), 3.71 (s, 3H), 3.58 (s, 2H), 3.15-2.59 (m,6H), 2.53 (s, 3H), 2.15 (s, 1H), 1.85-1.67 (m, 4H), 1.41-1.16 (m, 6H).LCMS (ESI) m/z: [M+H]+=862.

Example 9—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl)azetidine-3-carboxamide (Compound D3)

To a stirred mixture of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid trifluoroacetic acid salt(55.40 mg, 0.106 mmol, 1 equiv) and4-[(5-aminopentyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;trifluoroacetic acid salt (50 mg, 0.106 mmol, 1 equiv) in DCM (2 mL) wasadded DIEA (41.04 mg, 0.318 mmol, 3 equiv) and PyBOP (82.62 mg, 0.159mmol, 1.5 equiv). The mixture was stirred for 2 hours at roomtemperature, and then it was concentrated under vacuum. The residue waspurified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (15% Phase B up to35% in 8 minutes); Detector, UV). This resulted in 6 mg (6.98%) of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl)azetidine-3-carboxamide formate as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.53 (s, 1H), 7.76(s, 1H), 7.65-7.51 (m, 2H), 7.05 (dd, J=7.8, 6.0 Hz, 2H), 6.83 (s, 2H),5.11-5.02 (m, 1H), 4.57 (s, 1H), 4.36 (s, 2H), 4.10 (s, 4H), 3.95 (s,6H), 3.71 (s, 3H), 3.36-3.26 (m, 3H), 2.91-2.68 (m, 3H), 2.12 (d, J=10.0Hz, 1H), 1.76-1.67 (m, 2H), 1.60 (q, J=7.3, 6.8 Hz, 2H), 1.49 (d, J=7.1Hz, 2H). LCMS (ESI) m/z: [M+H]⁺=750.32.

Example 10—Preparation ofN-[8-[(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)formamido]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamideformic acid (Compound D4 Formic Acid)

To a stirred mixture of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid; trifluoroacetic acid salt (68.57 mg, 0.131 mmol, 1.50 equiv) andN-(8-aminooctyl)-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamidetrifluoroacetic acid salt (50.00 mg, 0.087 mmol, 1.00 equiv) in DCM(2.00 mL) was added DIEA (67.72 mg, 0.524 mmol, 6.00 equiv) and PyBOP(68.17 mg, 0.131 mmol, 1.50 equiv). The mixture was stirred for 2 hoursat room temperature, and then it was concentrated under vacuum. Theresidue was purified by Prep-HPLC (conditions: X Bridge Shield RP18 OBDColumn, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (20%Phase B up to 32% in 7 minutes); Detector, UV). This resulted inN-[8-[(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)formamido]octyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]acetamideformic acid (12 mg, 14.77%) as a white solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.53 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 7.87-7.78 (m, 1H),7.75 (s, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.44 (d,J=8.4 Hz, 1H), 6.80 (s, 2H), 5.15 (dd, J=12.6, 5.3 Hz, 1H), 4.76 (s,2H), 4.14 (s, 2H), 3.92 (s, 6H), 3.80 (s, 4H), 3.71 (s, 3H), 3.20 (t,J=7.0 Hz, 2H), 2.94-2.71 (m, 6H), 2.15 (s, 1H), 1.58 (d, J=7.9 Hz, 2H),1.51 (s, 2H), 1.35 (s, 8H).

LCMS (ESI) m/z: [M+H]⁺=850.37.

Example 11—Preparation ofN-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanamide(Compound D5)

To a solution of6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanoicacid (50.00 mg, 0.129 mmol, 1.00 eq.) and DIEA (49.92 mg, 0.386 mmol, 3eq.) in DCM (2.00 mL, 31.460 mmol, 244.37 eq.) was added PyBOP (100.49mg, 0.193 mmol, 1.5 eq.) and4-[4-[(3-aminoazetidin-1-yl)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(48.98 mg, 0.129 mmol, 1 eq.). The resulting solution was stirred atroom temperature for 1 hour. The crude product (50 mg) was purified byPrep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 10% B to 30% B in 8 minutes; 254 nm; Rt: 6.57minutes) to affordN-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanamide(14.8 mg, 15.31%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.54(s, 1H), 8.69 (d, J=5.7 Hz, 1H), 7.82-7.73 (m, 2H), 7.65-7.58 (m, 1H),7.44 (dd, J=7.9, 3.2 Hz, 2H), 6.83 (s, 2H), 5.10 (dd, J=12.4, 5.4 Hz,1H), 4.60-4.47 (m, 1H), 4.34 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 4.18 (s,2H), 3.94 (s, 8H), 3.71 (s, 3H), 2.87-2.64 (m, 3H), 2.30 (t, J=7.3 Hz,2H), 2.17-2.09 (m, 1H), 1.90 (p, J=6.4 Hz, 2H), 1.75 (p, J=7.4 Hz, 2H),1.61 (q, J=8.0 Hz, 2H). LCMS (ESI) m/z: [M+H]+=751.25.

Example 12—Preparation of4-[2-[1-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carbonyl)-[4,4-bipiperidin]-1-yl]-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione formic acid (CompoundD6 Formic Acid)

To a stirred mixture of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid trifluoroacetic acid salt (26.32 mg, 0.050 mmol, 1.50 equiv) and4-(2-[[4,4-bipiperidin]-1-yl]-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dionetrifluoroacetic acid salt (20.00 mg, 0.034 mmol, 1.00 equiv) in DCM (2mL) was added DIEA (26.00 mg, 0.201 mmol, 6.00 equiv) and PyBOP (26.17mg, 0.050 mmol, 1.50 equiv). The mixture was stirred for 2 hours at roomtemperature, and then it was concentrated under vacuum. The residue waspurified was purified by Prep-HPLC (conditions: X Select CSH Prep C18OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (8%Phase B up to 22% in 8 minutes); Detector, UV). This resulted in4-[2-[1-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carbonyl)-[4,4-bipiperidin]-1-yl]-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione formic acid (3.5 mg,10.89%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.54 (d, J=0.8Hz, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.56 (s, 1H), 7.84-7.72 (m, 2H), 7.63(d, J=5.8 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 6.81(s, 2H), 5.31-4.98 (m, 3H), 4.68-4.44 (m, 2H), 4.16 (s, 2H), 3.93 (s,10H), 3.79-3.56 (m, 5H), 3.09-2.93 (m, 2H), 2.93-2.61 (m, 6H), 2.15 (d,J=10.4 Hz, 1H), 1.86-1.67 (m, 4H), 1.50-1.25 (m, 3H), 1.23-1.04 (m, 2H).LCMS (ESI) m/z: [M+H]⁺=874.37.

Example 13—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-carboxamide formic acid (Compound D7Formic Acid)

To a stirred mixture of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid trifluoroacetic acid salt (75.73 mg, 0.145 mmol, 1.5 equiv) and4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dionetrifluoroacetic acid salt (50 mg, 0.096 mmol, 1 equiv) in DCM (2 mL) wasadded DIEA (74.79 mg, 0.579 mmol, 6 equiv) and PyBOP (75.28 mg, 0.145mmol, 1.5 equiv). The mixture was stirred for 2 hours at roomtemperature, and then it was concentrated under vacuum. The residue waspurified by Prep-HPLC (conditions: X Select CSH Prep C18 OBD Column, 5μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN (10% Phase B up to32% in 8 minutes); Detector, UV). This resulted in1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-carboxamideformic acid (13.2 mg, 15.77%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.53 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.56 (s, 1H), 7.75(s, 1H), 7.62 (d, J=5.9 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd,J=11.7, 7.8 Hz, 2H), 6.80 (s, 2H), 5.07 (dd, J=12.4, 5.5 Hz, 1H), 4.20(s, 2H), 3.92 (s, 10H), 3.78-3.57 (m, 9H), 3.61-3.43 (m, 4H), 3.41 (td,J=5.2, 1.6 Hz, 2H), 2.88 (ddd, J=19.0, 14.0, 5.0 Hz, 1H), 2.80-2.64 (m,3H). 2.17-2.08 (m, 1H). LCMS (ESI) m/z: [M+H]⁺=796.25.

Example 14—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamideformic acid (Compound D8 Formic Acid)

Step 1: Preparation of4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(i14-2)

To a solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione(500 mg, 1.810 mmol, 1 equiv) in DMF (10 mL) was added CH₃I (385.39 mg,2.715 mmol, 1.5 equiv) and K₂CO₃ (750.51 mg, 5.430 mmol, 3 equiv). Theresulting solution was stirred for overnight at 25° C. The solids werefiltered out. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:2). This resulted in4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(480 mg, 91.36%) as a white solid. LCMS (ESI) m/z: [M−H]+=291.

Step 2: Preparation of tert-butylN-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate(i14-3)

To a solution of4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(480 mg, 1.654 mmol, 1 equiv) and tert-butyl N-(8-aminooctyl)carbamate(404.14 mg, 1.654 mmol, 1 equiv) in NMP (10 mL) was added DIEA (641.21mg, 4.961 mmol, 3 equiv). The resulting solution was stirred for 6 hoursat 90° C. The resulting solution was diluted with 20 mL of water andextracted with ethyl acetate (2×20 mL), and the organic layers werecombined and dried over anhydrous sodium sulfate and concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in tert-butylN-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate(480 mg, 56.40%) as a green solid. LCMS (ESI) m/z: [M−H]+=515.

Step 3: Preparation of4-[(8-aminooctyl)amino]-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(i14-4)

A mixture of tert-butylN-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamate(150 mg, 0.291 mmol, 1 equiv) and 4 M HCl in 1,4-dioxane (5 mL) wasstirred for 1 hour at 25° C. The resulting mixture was concentrated.This resulted in4-[(8-aminooctyl)amino]-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(100 mg, 82.77%) as a white solid, that was used directly withoutfurther purification. LCMS (ESI) m/z: [M−H]+=415.

Step 4: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamideformic acid (Compound D8 Formic Acid)

To a solution of4-[(8-aminooctyl)amino]-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(80 mg, 0.193 mmol, 1 equiv) and1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid (79.02 mg, 0.193 mmol, 1 equiv) in DMF (3 mL) was added HATU(110.08 mg, 0.290 mmol, 1.5 equiv) and DIEA (49.89 mg, 0.386 mmol, 2equiv). The resulting solution was stirred for 2 hours at 25° C. Thecrude product was purified by Prep-HPLC (conditions: XBridge Prep C18OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN;Detector, UV 254 nm). This resulted in1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide(15 mg, 9.64%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.54(d, J=0.8 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.54 (s, 1.2H, FA), 7.77 (s,1H), 7.65-7.52 (m, 2H), 7.10-7.01 (m, 2H), 6.84 (s, 2H), 5.10 (dd,J=12.9, 5.4 Hz, 1H), 4.39 (s, 2H), 4.14 (d, J=8.2 Hz, 3H), 3.95 (s, 6H),3.71 (s, 3H), 3.54 (d, J=8.1 Hz, 1H), 3.22 (t, J=7.0 Hz, 2H), 3.17 (d,J=3.1 Hz, 1H), 3.15 (s, 3H), 2.99 (s, 1H), 2.96-2.86 (m, 2H), 2.69 (dt,J=12.7, 6.3 Hz, 2H), 2.15-2.05 (m, 1H), 1.68 (p, J=7.1 Hz, 2H), 1.52 (q,J=7.1 Hz, 2H), 1.38 (s, 8H). LCMS (ESI) m/z: [M−H]+=806.40.

Example 15—Preparation of2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamideformic acid (Compound D9 Formic Acid)

To a solution of2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)aceticacid (110 mg, 0.260 mmol, 1 equiv) in DMF (3 mL) was added4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(104.03 mg, 0.260 mmol, 1.00 equiv), PyBOP (202.77 mg, 0.390 mmol, 1.50equiv), and DIEA (167.86 mg, 1.299 mmol, 5.00 equiv). The resultingmixture was stirred at room temperature for 16 hours. Without workup,the crude product was purified by Prep-HPLC (conditions: SunFire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 27% B to 34% Bin 8 minutes; 254 nm; Rt: 6.28 minutes) to afford2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)acetamideformic acid (26.7 mg) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ9.52 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (s, 0.8H, FA), 7.76 (s, 1H),7.61 (d, J=5.7 Hz, 1H), 7.54 (dd, J=8.5, 7.1 Hz, 1H), 7.03 (dd, J=7.8,3.5 Hz, 2H), 6.85 (s, 2H), 5.06 (dd, J=12.4, 5.4 Hz, 1H), 4.43 (s, 2H),4.18 (t, J=9.5 Hz, 2H), 4.02-3.90 (m, 7H), 3.70 (s, 3H), 3.30 (d, J=6.8Hz, 2H), 3.17 (t, J=7.1 Hz, 3H), 2.97-2.62 (m, 3H), 2.58 (d, J=7.4 Hz,2H), 2.19-2.05 (m, 1H), 1.65 (q, J=7.0 Hz, 2H), 1.57-1.37 (m, 10H). LCMS(ESI) m/z: [M+H]⁺=806.25.

Example 16—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide (D10)

To a stirred solution of(R)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid (40.9 mg, 0.100 mmol, 1 equiv), DIEA (64.55 mg, 0.499 mmol, 5equiv), and PyBOP (155.95 mg, 0.300 mmol, 3 equiv) in DMF (1 mL) wasadded4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dionehydrochloride (43.65 mg, 0.100 mmol, 1 equiv) at ambient atmosphere. Themixture was stirred for 1 hour at room (conditions: XBridge Shield RP18OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), MobilePhase B: ACN; Flow rate: 25 mL/minuteute; Gradient: 18% B to 35% B in 12minutes; 254/220 nm; R_(t): 11.74 minutes) to afford(R)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide(25 mg, 31.60%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.52(s, 1H), 8.68 (d, J=5.8 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J=5.8 Hz, 1H),7.54 (dd, J=8.5, 7.1 Hz, 1H), 7.01 (t, J=7.8 Hz, 2H), 6.78 (s, 2H), 5.06(dd, J=12.3, 5.5 Hz, 1H), 4.17 (s, 2H), 3.93 (s, 6H), 3.97-3.82 (m, 1H),3.74 (s, 2H), 3.69 (s, 3H), 3.31-3.09 (m, 4H), 2.97-2.62 (m, 3H), 2.50(d, J=9.2 Hz, 1H), 2.32-2.20 (m, 1H), 2.19-2.09 (m, 1H), 1.57 (q, J=6.9Hz, 2H), 1.45-1.30 (m, 10H). LCMS (ESI) m/z: [M+H]+=792.20.

Example 17—Preparation of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide(Compound D11)

To a solution of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-2-carboxylicacid (50.00 mg, 0.122 mmol, 1.00 equiv) and4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(48.91 mg, 0.122 mmol, 1.00 equiv) in DMF (2.00 mL) was added PyBOP(127.10 mg, 0.244 mmol, 2.00 equiv) and DIEA (47.35 mg, 0.366 mmol, 3.00equiv). The resulting solution was stirred at 25° C. for 2 hours. Thecrude product was purified by preparative HPLC (condition: XSelect CSHPrep C18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 25 mL/minuteute; Gradient: 20% B to 55%B in 8 minutes; 254 nm; R_(t): 7.12 minutes). Fractions containing thedesired compound were evaporated to dryness to afford(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide(35 mg, 35.47%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.51(s, 1H), 8.68 (d, J=5.7 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=5.8 Hz, 1H),7.53 (t, J=7.8 Hz, 1H), 7.00 (dd, J=10.6, 7.8 Hz, 2H), 6.75 (s, 2H),5.05 (dd, J=12.4, 5.4 Hz, 1H), 3.89 (s, 9H), 3.69 (s, 3H), 3.30 (s, 2H),3.25 (t, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.94-2.64 (m, 3H), 2.35(d, J=9.5 Hz, 1H), 2.16-2.00 (m, 1H), 1.58 (t, J=7.1 Hz, 2H), 1.40 (d,J=6.7 Hz, 2H), 1.30 (s, 8H). LCMS (ESI) m/z: [M+H]+=792.60.

Example 18—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide(Compound D12)

Step 1: Preparation of tert-butyl3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-H-isoindol-4-yl]amino]octyl)sulfamoyl]azetidine-1-carboxylate(i18-2)

To a solution of4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(100.00 mg, 0.250 mmol, 1.00 equiv) in DCM (2.00 mL) was addedtert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (95.78 mg, 0.375mmol, 1.50 equiv) and TEA (50.53 mg, 0.499 mmol, 2.00 equiv) at 0° C.The resulting solution was stirred for 2 hours at 25° C. The reactionwas then quenched by the addition of 5 mL of MeOH. The resulting mixturewas concentrated. The residue was applied onto a silica gel column withethyl DCM/MeOH (20:1). This resulted in 110 mg (71.08%) of tert-butyl3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)sulfamoyl]azetidine-1-carboxylate as a yellow solid. LCMS (ESI) m/z:[M+H]+=620.

Step 2: Preparation ofN-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-3-sulfonamide(i18-3)

A solution of tert-butyl3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)sulfamoyl]azetidine-1-carboxylate (110.00 mg, 0.177 mmol, 1.00 equiv) inTFA (2.00 mL) and CH₂Cl₂ (2.00 mL) was stirred at 0° C. for 1 hour. Theresulting mixture was concentrated under reduced pressure to affordN-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-3-sulfonamide(85 mg, 92.16%) as a yellow solid, which was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=520.

Step 3: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide(Compound D12)

To a solution ofN-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide(85.00 mg, 0.164 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(53.06 mg, 0.164 mmol, 1.00 equiv) in MeOH (2.00 mL) was added NaBH₃CN(20.56 mg, 0.327 mmol, 2.00 equiv). The resulting solution was stirredat 25° C. for 2 hours. The crude product was purified by preparativeHPLC Column (condition: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minuteutes; Gradient: 20% B to 55% B in 8 minutes; 254 nm; R_(t):7.12 minutes). Fractions containing the desired compound were evaporatedto dryness to afford1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-sulfonamide(50 mg, 36.92%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.52(d, J=0.9 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.53 (s, 0.47H, FA), 7.74 (s,1H), 7.63 (dd, J=5.8, 0.9 Hz, 1H), 7.55 (dd, J=8.5, 7.1 Hz, 1H), 7.03(dd, J=7.8, 4.8 Hz, 2H), 6.77 (s, 2H), 5.06 (dd, J=12.5, 5.5 Hz, 1H),4.03 (p, J=8.2, 7.8 Hz, 1H), 3.91 (d, J=4.1 Hz, 2H), 3.89 (s, 6H),3.78-3.68 (m, 8H), 3.30 (d, J=6.8 Hz, 1H), 3.03 (t, J=7.0 Hz, 2H),2.94-2.80 (m, 1H), 2.80-2.66 (m, 2H), 2.17-2.08 (m, 1H), 1.70-1.62 (m,2H), 1.51 (d, J=6.9 Hz, 2H), 1.44-1.37 (m, 8H). LCMS (ESI) m/z:[M+H]+=828.35.

Example 19—Preparation of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-3-methylazetidine-3-carboxamide(Compound D13)

Step 1: Preparation of methyl1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-3-methylazetidine-3-carboxylate(i19-2)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(200 mg, 0.617 mmol, 1 equiv) and methyl 3-methylazetidine-3-carboxylate(79.65 mg, 0.617 mmol, 1.00 equiv) in MeOH (2 mL) was added NaBH₃CN(77.50 mg, 1.233 mmol, 2 equiv). The resulting solution was stirred at25° C. for 1 hour. The residue was purified by silica gel columnchromatography, eluted with DCM/MeOH (9:1) to afford methyl 1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl) phenyl]methyl]-3-methylazetidine-3-carboxylate (247 mg, 91.56%) as a yellowsolid. LCMS (ESI) m/z: [M+H]+=438.

Step 2: Preparation of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-3-methylazetidine-3-carboxylicacid (i19-3)

A solution of methyl1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-methylazetidine-3-carboxylate(235 mg, 0.537 mmol, 1 equiv) in HCl (12 M, 5 mL) was stirred at 25° C.for 40 minutes. The mixture was concentrated under reduced pressureafford1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-methylazeti-dine-3-carboxylicacid (185 mg, 81.33%) as a brown solid, that was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=424.

Step 3: Preparation of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-3-methylazetidine-3-carboxamide(Compound D13)

To a solution of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-methylazetidine-3-carboxylicacid (50 mg, 0.118 mmol, 1 equiv),4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(94.57 mg, 0.236 mmol, 2 equiv) and Et₃N (119.48 mg, 1.181 mmol, 10.00equiv) in DMF (3 mL), was added EDCI (27.16 mg, 0.142 mmol, 1.2 equiv)and HOBT (19.15 mg, 0.142 mmol, 1.2 equiv), the resulting solution wasstirred at 25° C. for 24 hours. The crude product was purified byPrep-HPLC with the following conditions (condition: XBridge Prep C18 OBDColumn, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) and ACN;Detector, UV) to give1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-3-methylazetidine-3-carboxamide(21.7 mg, 22.80%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ9.53 (s, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.62(d, J=5.7 Hz, 1H), 7.59-7.49 (m, 1H), 7.07-6.98 (m, 2H), 6.81 (s, 2H),5.06 (dd, J=12.3, 5.4 Hz, 1H), 4.19 (s, 2H), 4.06 (s, 2H), 3.93 (s, 6H),3.71 (s, 5H), 3.32-3.16 (m, 1H), 2.92-2.66 (m, 4H), 2.15-2.06 (m, 1H),1.64 (d, J=7.4 Hz, 2H), 1.55 (s, 5H), 1.39-1.32 (m, 8H). LCMS (ESI) m/z:[M+H]+=806.50.

Example 20—Preparation of1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-N-methylazetidine-3-carboxamide(Compound D14)

Step 1: Preparation of tert-butylN-[8-(1,3-dioxoisoindol-2-yl)octyl]carbamate (i20-2)

A mixture of tert-butyl N-(8-aminooctyl)carbamate (1.00 g, 4.092 mmol,1.00 equiv) and phthalic anhydride (606.10 mg, 4.092 mmol, 1.00 equiv)in toluene (20.00 mL) was stirred for 2 hours at 130° C. under nitrogenatmosphere. The mixture was allowed to cool down to room temperature andthe solvent was evaporated. The resulting residue was purified by silicagel column chromatography, eluted with PE/EtOAc (10:1) to affordtert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]carbamate (1.7 g, 95.41%)as a white solid. LCMS (ESI) m/z: [M+H]+=375.

Step 2: Preparation of tert-butylN-[8-(1,3-dioxoisoindol-2-yl)octyl]-N-methylcarbamate (i20-3)

To a stirred solution of tert-butylN-[8-(1,3-dioxoisoindol-2-yl)octyl]carbamate(1.24 g, 3.311 mmol, 1.00equiv) in DMF (1.00 mL) was added NaH (0.16 g, 6.622 mmol, 2 equiv) inportions at 0° C. under nitrogen atmosphere. Then CH₃I (1.88 g, 13.245mmol, 4 equiv) was added. The resulting mixture was stirred for 1 hourat room temperature under nitrogen atmosphere. The residue was purifiedby silica gel column chromatography, eluted with PE/EtOAc (12:1) toafford tert-butyl N-[8-(1,3-dioxoisoindol-2-yl)octyl]-N-methylcarbamate(800 mg, 62.19%) as a colorless liquid. LCMS (ESI) m/z: [M+H]+=389.

Step 3: Preparation of tert-butyl N-(8-aminooctyl)-N-methylcarbamate(i20-4)

A solution of tert-butylN-[8-(1,3-dioxoisoindol-2-yl)octyl]-N-methylcarbamate (700.00 mg, 1.802mmol, 1.00 equiv) and NH₂NH₂ (259.84 mg, 3.604 mmol, 2 equiv) in EtOH(5.00 mL) was stirred for 1 hour at 90° C. under nitrogen atmosphere.The mixture was allowed to cool down to room temperature. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography,eluted with PE/EtOAc (12:1) to afford tert-butylN-(8-aminooctyl)-N-methylcarbamate (580 mg, 94.68%) as a colorlessliquid. LCMS (ESI) m/z: [M+H]+=259.

Step 4: Preparation of tert-butylN-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)-N-methylcarbamate(i20-5)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (520.00 mg,1.883 mmol, 1.00 equiv) and tert-butylN-(8-aminooctyl)-N-methylcarbamate (486.46 mg, 1.883 mmol, 1 equiv) inDMF (5.00 mL) was added DIPEA (1216.53 mg, 9.413 mmol, 5 equiv). Thesolution was stirred for 1 hour at 90° C. under nitrogen atmosphere,then it was cooled down to room temperature. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with CH₂Cl₂/MeOH (12:1) to affordtert-butylN-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)-N-methylcarbamate(260 mg, 26.84%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=515.

Step 5: Preparation of2-(2,6-dioxopiperidin-3-yl)-4-[[8-(methylamino)octyl]amino]isoindole-1,3-dione(i20-6)

A solution of tert-butylN-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)-N-methylcarbamate(220.00 mg, 0.427 mmol, 1.00 equiv) in 4 M HCl in dioxane (6.00 mL) wasstirred for 2 hours at room temperature. The solvent was evaporated andthe residue was purified by reverse flash chromatography (condition: C18silica gel column; mobile phase, MeOH in water, 10% to 50% gradient in10 minutes; detector, UV 254 nm) to afford2-(2,6-dioxopiperidin-3-yl)-4-[[8-(methylamino)octyl]amino]isoindole-1,3-dione(170 mg, 95.94%) as a dark yellow oil. LCMS (ESI) m/z: [M+H]+=415.

Step 6: Preparation of1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-N-methylazetidine-3-carboxamide(Compound D14)

To a stirred solution of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid (30 mg, 0.073 mmol, 1 equiv) in DMF (0.5 mL), was added DIPEA(47.35 mg, 0.366 mmol, 5 equiv), HATU (55.72 mg, 0.147 mmol, 2 equiv),and2-(2,6-dioxopiperidin-3-yl)-4-[[8-(methylamino)octyl]amino]-2,3-dihydro-1H-isoindole-1,3-dione(30.37 mg, 0.073 mmol, 1 equiv). The reaction was stirred at ambientatmosphere for 1 hour. The mixture was purified directly by Prep-HPLC(condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minuteutes; Gradient: 24% B to 36% B in 8 minutes; 254 nm; R_(t): 7.9minutes) to afford1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)-N-methylazetidine-3-carboxamideformate (25 mg, 40.05%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4)δ 9.52 (dd, J=4.5, 0.9 Hz, 1H), 8.68 (dd, J=5.8, 2.5 Hz, 1H), 8.56 (s,0.5H, FA), 7.75 (d, J=2.0 Hz, 1H), 7.67-7.58 (m, 1H), 7.53 (ddd, J=8.5,7.1, 4.7 Hz, 1H), 7.07-6.95 (m, 2H), 6.81 (d, J=1.8 Hz, 2H), 5.06 (ddd,J=12.1, 5.4, 2.5 Hz, 1H), 4.21 (d, J=4.7 Hz, 2H), 4.00 (dd, J=17.1, 8.8Hz, 4H), 3.93 (s, 6H), 3.80 (t, J=8.2 Hz, 1H), 3.70 (d, J=3.3 Hz, 3H),3.45-3.19 (m, 2H), 2.94 (d, J=4.3 Hz, 3H), 2.91-2.68 (m, 3H), 2.12 (s,1H), 1.67 (s, 2H), 1.57 (d, J=6.9 Hz, 2H), 1.41-1.33 (m, 8H). LCMS (ESI)m/z: [M+H]+=806.35.

Example 21—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl)-N-methylazetidine-3-carboxamideformic acid (Compound D15 Formic Acid)

To a solution of2-(2,6-dioxopiperidin-3-yl)-4-[[5-(methylamino)pentyl]amino]-2,3-dihydro-1H-isoindole-1,3-dione(60.00 mg, 0.161 mmol, 1.00 equiv),1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid (65.96 mg, 0.161 mmol, 1.00 equiv), and DIEA (41.64 g, 0.322 mmol,2.00 equiv) in DMF (2.00 mL, 25.844 mmol, 160.41 equiv) was added HATU(91.89 mg, 0.242 mmol, 1.50 equiv). The resulting mixture was stirred atroom temperature for 16 hours. Without workup, the crude product waspurified by Prep-HPLC (condition: XBridge Shield RP18 OBD Column 30*150mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 40 mL/minuteute; Gradient: 18% B to 18% B in 2 minutes; 254/220nm; R_(t): 11.43 minutes) to afford1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-y)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]pentyl)-N-methylazetidine-3-carboxamide;formic acid (25.1 mg) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ9.53 (dd, J=5.4, 0.9 Hz, 1H), 8.68 (dd, J=5.8, 1.2 Hz, 1H), 8.56 (s,0.53H, FA), 7.79-7.73 (m, 1H), 7.67-7.50 (m, 2H), 7.09-6.99 (m, 2H),6.80 (d, J=3.2 Hz, 2H), 5.06 (ddd, J=12.3, 5.4, 2.8 Hz, 1H), 4.17 (s,2H), 3.92-3.90 (m, 10H), 3.78 (q, J=9.0, 8.5 Hz, 1H), 3.71 (d, J=2.2 Hz,3H), 3.48-3.35 (m, 2H), 3.27 (t, J=7.5 Hz, 1H), 2.98-2.85 (m, 3H),2.89-2.64 (m, 4H), 2.22-2.08 (m, 1H), 1.75-1.62 (m, 4H), 1.43 (s, 2H).

LCMS (ESI) m/z: [M+H]⁺=764.45.

Example 22—Preparation of2-(2,6-dihydroxypiperidin-3-yl)-4-[(8-[[hydroxy(1-[[4-(6-hydroxy-1,5-dimethyl-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]amino]octyl)amino]-2,3-dihydro-1H-isoindole-1,3-diolformic acid (Compound D16 Formic Acid)

Step 1: Preparation of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(i22-2)

To a solution of 5-bromo-1,3-dimethylpyridin-2-one (1.00 g, 4.949 mmol,1.00 equiv) and bis(pinacolato)diboron (1508.17 mg, 5.939 mmol, 1.20equiv) in dioxane (10.00 mL) was added KOAc (971.46 mg, 9.898 mmol, 2.00equiv) and Pd(dppf)Cl₂·CH₂Cl₂ (404.18 mg, 0.495 mmol, 0.10 equiv). Afterstirring for 2 hours at 90° C. under a nitrogen atmosphere, theresulting mixture was concentrated under reduced pressure. The crudeproduct was used in the next step directly without further purification.LCMS (ESI) m/z: [M+H]+=250.

Step 2: Preparation of4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (i22-3)

To a solution of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(1.20 g, 4.817 mmol, 1.00 equiv) and 4-bromo-2,6-dimethoxybenzaldehyde(1.18 g, 4.817 mmol, 1.00 equiv) in 1,4-dioxane (40.00 mL) and H₂O (4.00mL) was added CS₂CO₃ (3.14 g, 9.634 mmol, 2.00 equiv) and Pd(dppf)Cl₂(0.35 g, 0.482 mmol, 0.10 equiv). After stirring for 2 hours at 80° C.under a nitrogen atmosphere, the resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (18:1) to afford4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (1.43 g,87.83%) as a brown syrup. LCMS (ESI) m/z: [M+H]+=288.

Step 3: Preparation of methyl1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylate(i22-4)

To a solution of methyl azetidine-3-carboxylate hydrochloride (1.13 g,7.466 mmol, 1.50 equiv) in MeOH (10.00 mL) was added Et₃N to pH 7-8.Then 4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxybenzaldehyde (1.43g, 4.977 mmol, 1.00 equiv) was added. After stirring for 5-10 minutes,NaBH₃CN (0.63 g, 9.954 mmol, 2.00 equiv) was added in portions atambient atmosphere. The resulting mixture was concentrated afterstirring for 1 hour at room temperature. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) toafford methyl1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylate(1.06 g, 52.36%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=387.

Step 4: Preparation of1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylicacid (i22-5)

A mixture of methyl1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylate(203.00 mg, 0.525 mmol, 1.00 equiv) in HCl (12 N, 2.00 mL) was stirredfor 2 hours at 90° C. The resulting mixture was concentrated underreduced pressure to give1-[[4-(1,5-dimethyl-6-oxopyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylicacid (150 mg, 71.31%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=373.

Step 4: Preparation of2-(2,6-dihydroxypiperidin-3-yl)-4-[(8-[[hydroxy(1-[[4-(6-hydroxy-1,5-dimethyl-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]amino]octyl)amino]-2,3-dihydro-1H-isoindole-1,3-diolformic acid (Compound D16 Formic Acid)

To a stirred mixture of1-[[4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidine-3-carboxylicacid trifluoroacetic acid (50 mg, 0.103 mmol, 1 equiv) and4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dionehydrochloride (44.91 mg, 0.103 mmol, 1 equiv) in DCM (2 mL) was addedDIEA (53.57 mg, 0.415 mmol, 4 equiv). After stirring for 10 minutes,PyBOP (80.89 mg, 0.155 mmol, 1.5 equiv) was added. The resulting mixturewas concentrated under reduced pressure, and then the residue waspurified by Prep-HPLC (conditions: Sun Fire C18 OBD Prep Column, 19mm×250 mm; mobile phase, Water (0.1% FA) and ACN (23% Phase B up to 33%in 8 min, hold 33% in 1 minutes); Detector, UV). This resulted in2-(2,6-dihydroxypiperidin-3-yl)-4-[(8-[[hydroxy(1-[[4-(6-hydroxy-1,5-dimethyl-1,6-dihydropyridin-3-yl)-2,6-dimethoxyphenyl]methyl]azetidin-3-yl)methyl]amino]octyl)amino]-2,3-dihydro-1H-isoindole-1,3-diolformic acid (2.4 mg, 2.73%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 8.56 (s, 2H, FA), 7.96 (s, 1H), 7.83 (s, 1H), 7.61-7.50(m, 1H), 7.04 (d, J=7.7 Hz, 2H), 6.88 (s, 2H), 4.62 (s, 1H), 4.32 (s,2H), 4.09 (d, J=7.9 Hz, 4H), 3.98 (s, 6H), 3.68 (s, 3H), 3.55-3.44 (m,2H), 3.21 (t, J=7.0 Hz, 2H), 2.91-2.68 (m, 4H), 2.22 (s, 3H), 2.12 (s,1H), 1.68 (s, 2H), 1.64-1.39 (m, 10H). LCMS (ESI) m/z: [M+H]⁺=373.17.

Example 23—Preparation of3-amino-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide(Compound D17)

Step 1: Preparation of 1-tert-Butyl 3-ethyl3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-1,3-dicarboxylate(23-2)

To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate(120 mg, 0.491 mmol, 1 equiv) and 2,5-dioxopyrrolidin-1-yl(9H-fluoren-9-yl)methyl carbonate (182.3 mg, 0.540 mmol, 1.1 equiv) inDCM (1 mL) was added TEA (149.1 mg, 1.474 mmol, 3 equiv). The resultingsolution was stirred at room temperature for 1 hour. The residue waspurified by Prep-TLC (PE/EtOAc 1:1) to afford 1-tert-butyl 3-ethyl3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-1,3-dicarboxylate(120mg, 48%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=467.

Step 2: Preparation of ethyl3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate(i23-3)

A mixture of 1-tert-butyl 3-ethyl3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-1,3-dicarboxylate(120.00 mg, 0.257 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (2 mL)was stirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to afford ethyl3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate(120 mg, 89%) as a white solid that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=367.

Step 3: Preparation of Ethyl1-[[2,6-Dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate(23-4)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(127.5 mg, 0.393 mmol, 1.20 equiv) and ethyl3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate(120 mg, 0.327 mmol, 1 equiv) in MeOH (1 mL) was added NaBH₃CN (41.2 mg,0.655 mmol, 2 equiv). The resulting solution was stirred at roomtemperature for 1 hour. The mixture was then concentrated under reducedpressure and the residue was purified by Prep-TLC (CH₂Cl₂/MeOH 12:1) toafford ethyl1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate(100 mg, 45%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=675.

Step 4: Preparation of Ethyl1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylicacid (i23-5)

A solution of ethyl1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylate(100 mg, 0.148 mmol, 1 equiv) in concentrated HCl (2 mL) was stirred at90° C. for 1 hour. The resulting mixture was concentrated under reducedpressure to afford1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylicacid (100 mg, 94%) as a yellow solid that was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=647.3

Step 5: Preparation of (9H-fluoren-9-yl)methylN-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamoyl]azetidin-3-yl)carbamate (i23-7)

To a solution of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)azetidine-3-carboxylicacid (100 mg, 0.155 mmol, 1 equiv) and4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(74.3 mg, 0.186 mmol, 1.2 equiv) in DMF (1 mL) was added DIEA (60.0 mg,0.464 mmol, 3 equiv) and HATU (88.2 mg, 0.232 mmol, 1.5 equiv). Theresulting solution was stirred at room temperature for 1 hour. Themixture was then concentrated under reduced pressure and the residue waspurified by Prep-TLC (CH₂Cl₂/MeOH 12:1) to afford(9H-fluoren-9-yl)methylN-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamoyl]azetidin-3-yl)carbamate (90 mg, 51%) as a yellow solid. LCMS (ESI) m/z:[M+H]+=1029.

Step 6: Preparation of3-Amino-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide(Compound D17)

A solution of (9H-fluoren-9-yl)methylN-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-3-[(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)carbamoyl]azetidin-3-yl)carbamate(90 mg, 0.087 mmol, 1.00 equiv) in piperidine (1 mL) and DMF (4 mL) wasstirred at room temperature for 1 hour. The crude solution was purifiedby Prep-HPLC (condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minuteute; Gradient: 28% B to 28% B in 2 minutes; 254 nm;R_(t): 6.9 minutes) to afford3-amino-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)azetidine-3-carboxamide(3.8 mg, 5.2%) as a yellow solid. ¹H NMR (300 MHz, Acetonitrile-d3) δ9.52 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.26 (s, 0.53H, FA), 7.78-7.42 (m,4H), 7.02 (dd, J=7.8, 4.2 Hz, 2H), 6.75 (s, 2H), 6.30 (t, J=5.9 Hz, 1H),4.95 (dd, J=12.4, 5.2 Hz, 1H), 4.10 (s, 2H), 3.95 (d, J=8.8 Hz, 2H),3.87 (s, 6H), 3.50 (s, 3H), 3.24 (dq, J=23.4, 6.6 Hz, 4H), 2.83-2.59 (m,3H), 1.63 (s, 2H), 1.49 (s, 2H), 1.32 (d, J=13.1 Hz, 10H). LCMS (ESI)m/z: [M+H]+=807.40.

Example 24—Preparation of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide(Compound D18)

Compound D11 was further separated by chiral HPLC to afford(2S)-1-((2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl)methyl)-N-(8-((2-((R)-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octyl)azetidine-2-carboxamide (10 mg, 10.34%) as a yellow solid. ¹H NMR (400MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 7.72 (s, 1H),7.62 (d, J=5.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.00 (dd, J=10.6, 7.8Hz, 2H), 6.75 (s, 2H), 5.05 (dd, J=12.4, 5.4 Hz, 1H), 3.89 (s, 9H), 3.69(s, 3H), 3.30 (s, 2H), 3.25 (t, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H),2.94-2.64 (m, 3H), 2.35 (d, J=9.5 Hz, 1H), 2.16-2.00 (m, 1H), 1.58 (t,J=7.1 Hz, 2H), 1.40 (d, J=6.7 Hz, 2H), 1.30 (s, 8H). LCMS (ESI) m/z:[M+H]+=792.60.

Example 25—Preparation of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octyl)azetidine-2-carboxamide(Compound D19)

Compound D11 was further separated by chiral HPLC to afford(2S)-1-((2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl)methyl)-N-(8-((2-((S)-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)octyl)azetidine-2-carboxamide (10 mg, 10.34%) as a yellow solid. ¹H NMR (400MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 7.72 (s, 1H),7.62 (d, J=5.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.00 (dd, J=10.6, 7.8Hz, 2H), 6.75 (s, 2H), 5.05 (dd, J=12.4, 5.4 Hz, 1H), 3.89 (s, 9H), 3.69(s, 3H), 3.30 (s, 2H), 3.25 (t, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H),2.94-2.64 (m, 3H), 2.35 (d, J=9.5 Hz, 1H), 2.16-2.00 (m, 1H), 1.58 (t,J=7.1 Hz, 2H), 1.40 (d, J=6.7 Hz, 2H), 1.30 (s, 8H). LCMS (ESI) m/z:[M+H]+=792.60

Example 26—Preparation of6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)spiro[3.3]heptane-2-carboxamide(Compound D20)

Step 1: Preparation of methyl 2-azaspiro[3.3]heptane-6-carboxylatetrifluoroacetic acid (i26-2)

A mixture of 2-tert-butyl 6-methyl2-azaspiro[3.3]heptane-2,6-dicarboxylate (127.60 mg, 0.500 mmol, 1.00equiv) and TFA (1 mL) in DCM (3.00 mL) was stirred for 2 hours at roomtemperature. Then, the solvent was evaporated, and the resulting residuewas used in the next step directly without further purification. LCMS(ESI) m/z: [M+H]+=156.

Step 2: Preparation of methyl2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylate(i26-4)

To a stirred solution of methyl 2-azaspiro[3.3]heptane-6-carboxylatetrifluoroacetic acid (77.60 mg, 0.288 mmol, 1.00 equiv), Et₃N (116.67mg, 1.153 mmol, 4 equiv), and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(93.49 mg, 0.288 mmol, 1 equiv) in MeOH (2.00 mL) was added NaBH₃CN(36.23 mg, 0.576 mmol, 2 equiv) in portions at room temperature. Afterthe solvent was evaporated, the residue was purified by silica gelcolumn chromatography, eluted with CH₂Cl₂/MeOH (12:1) to afford methyl2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylate(156 mg, 96.91%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=464.

Step 3: Preparation of2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylicacid (i26-5)

A solution of methyl2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylate(156.00 mg, 0.347 mmol, 1.00 equiv) and LiOH (83.28 mg, 3.47 mmol, 10.0equiv) in mixed THF (2.00 mL) and H₂O (1.00 mL) was stirred for 1 hourat room temperature. Then solvent was evaporated, and the resultingsolution was purified by Prep-HPLC (0-100% ACN/water, with 0.1% TFA) toafford2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2-azaspiro[3.3]heptane-6-carboxylic acid (114.7 mg, 75.89%) as a dark yellow oil. LCMS(ESI) m/z: [M+H]+=450.

Step 4: Preparation of6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)spiro[3.3]heptane-2-carboxamide(Compound D20)

To a stirred solution of6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]spiro[3.3]heptane-2-carboxylicacid (45 mg, 0.100 mmol, 1 equiv) and4-[(8-aminooctyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(40.00 mg, 0.100 mmol, 1 equiv) in DMF (0.5 mL), was added DIEA (64.54mg, 0.499 mmol, 5 equiv) and PyBOP (103.95 mg, 0.200 mmol, 2 equiv) atroom temperature. The mixture was stirred for 1 h and directly purifiedby Prep-HPLC with the following conditions (conditions: SunFire C18 OBDPrep Column, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile PhaseB: ACN; Flow rate: 25 mL/minuteute; Gradient: 29% B to 32% B in 8minutes; 254 nm; R_(t): 6.55 minutes) to afford6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]octyl)spiro[3.3]heptane-2-carboxamide(14.1 mg, 14.24%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ9.54 (d, J=0.9 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 7.78 (s, 1H), 7.65-7.50(m, 2H), 7.04 (d, J=7.9 Hz, 2H), 6.86 (s, 2H), 5.05 (dd, J=12.6, 5.7 Hz,1H), 4.63 (s, 2H), 4.44 (s, 2H), 4.18 (s, 3H), 3.97 (s, 6H), 3.88 (s,1H), 3.71 (s, 3H), 3.34-3.11 (m, 3H), 3.10-2.67 (m, 5H), 2.61-2.37 (m,4H), 2.27-2.13 (m, 1H), 1.67 (q, J=7.0 Hz, 2H), 1.59-1.26 (m, 10H). LCMS(ESI) m/z: [M+H]+=832.5.

Example 27—Preparation of6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]hexyl)spiro[3.3]heptane-2-carboxamide(Compound D21)

Step 1: Preparation o tert-butylN-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl)carbamate (i27-2)

To a stirred solution of pomalidomide (150.30 mg, 0.550 mmol, 1.00equiv) and tert-butyl N-(6-bromohexyl)carbamate (154.13 mg, 0.550 mmol,1 equiv) in DMF (1.00 mL) was added K₂CO₃ (152.04 mg, 1.100 mmol, 2equiv) at room temperature. The resulting mixture was stirred overnightat room temperature, and then it was concentrated and purified by silicagel column chromatography, elutinged with PE/EtOAc (10:1) to affordtert-butylN-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl)carbamate (293 mg, 95.82%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=473.

Step 2: Preparation of4-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dionetrifluoroacetic acid (i27-3)

A solution of tert-butylN-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl)carbamate (293.00 mg, 0.620 mmol, 1.00 equiv) and TFA (2.0 mL) in DCM(5.00 mL) was stirred for 1 h at room temperature. The mixture was thenconcentrated to afford4-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(243 mg, 80.56%) as a yellow semi-solid, that was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=373.

Step 3: Preparation of6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]hexyl)spiro[3.3]heptane-2-carboxamide (Compound D21)

To a stirred solution of6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]spiro[3.3]heptane-2-carboxylicacid (30 mg, 0.067 mmol, 1 equiv) in DMF (0.5 mL) was added DIEA (43.03mg, 0.333 mmol, 5 equiv), PyBOP (69.30 mg, 0.133 mmol, 2 equiv), and4-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(24.80 mg, 0.067 mmol, 1 equiv). The reaction was stirred at ambientatmosphere for 1 hour. The mixture was purified directly by Prep-HPLC(condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minuteute; Gradient: 12% B to 38% B in 8 minutes; 254 nm; R_(t): 7.58minutes), to afford6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2,4a,8a-tetrahydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]hexyl)spiro[3.3]heptane-2-carboxamide(11.2 mg, 20.90%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ9.52 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=5.8 Hz,1H), 7.50-7.39 (m, 1H), 7.01 (dd, J=17.7, 7.7 Hz, 2H), 6.85 (s, 2H),5.09 (dd, J=12.9, 5.5 Hz, 1H), 4.42 (s, 2H), 4.16 (d, J=3.1 Hz, 4H),3.96 (s, 6H), 3.78 (t, J=7.4 Hz, 2H), 3.71 (s, 3H), 3.50 (q, J=7.3 Hz,1H), 3.20 (qd, J=7.3, 5.4 Hz, 9H), 2.99-2.87 (m, 2H), 2.91-2.83 (m, 1H),2.75-2.61 (m, 1H), 2.53 (s, 2H), 2.53-2.47 (m, 1H), 2.47-2.37 (m, 2H),2.22-2.09 (m, 2H), 1.94 (s, 2H), 1.93 (s, 6H), 1.61 (s, 1H), 1.51 (tt,J=15.1, 8.0 Hz, 4H), 1.46-1.26 (m, 23H), 1.12 (t, J=7.3 Hz, 10H), 0.91(q, J=9.7, 7.9 Hz, 3H). LCMS (ESI) m/z: [M+H]+=804.40.

Example 28—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl)azetidine-3-sulfonamide formic acid (Compound D22 Formic Acid)

Step 1: Preparation oftert-butyl-3-[(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]butyl)sulfamoyl]azetidine-1-carboxylate(i28-2)

To a stirred mixture of5-[(4-aminobutyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(60.00 mg, 0.174 mmol, 1.00 equiv) and tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate (111.38 mg, 0.436 mmol, 2.50equiv) in DCM (2.00 mL) was added TEA (52.89 mg, 0.523 mmol, 3.00equiv). After stirring for 1.5 hours at room temperature, the resultingmixture was concentrated under reduced pressure. The residue waspurified by Prep-TLC (CH₂Cl₂/EtOAc (1:2)) to affordtert-butyl-3-[(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]butyl)sulfamoyl]azetidine-1-carboxylate(78mg, 73.87%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=564.20.

Step 2: Preparation ofN-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)azetidine-3-sulfonamide(i28-3)

To a stirred mixture oftert-butyl-3-[(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]butyl)sulfamoyl]azetidine-1-carboxylate(78.00 mg, 0.138 mmol, 1.00 equiv) in DCM (2.00 mL, 0.012 mmol, 0.10equiv) was added TFA (0.40 mL, 5.385 mmol, 38.91 equiv). After stirringfor 1 hour at room temperature, the resulting mixture was concentratedunder reduced pressure. The residue was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]⁺=464.15.

Step 3: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl)azetidine-3-sulfonamideformic acid (Compound D38 Formic Acid)

A mixture ofN-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl)azetidine-3-sulfonamide (64.17 mg, 0.138 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(44.90 mg, 0.138 mmol, 1.00 equiv) in DMF (2 mL) was stirred at roomtemperature, then adjusted to pH 8˜9 by addition of TEA. The abovemixture was added NaBH₃CN (26.10 mg, 0.415 mmol, 3.00 equiv) inportions, the resulting mixture was stirred for 2 hours at roomtemperature. The resulting mixture was concentrated under reducedpressure, the residue was purified by Prep-HPLC (condition: X Select CSHPrep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA) andACN (15% Phase B up to 30% in 14 minutes); Detector, UV). This resultedin 15 mg (12.59%) of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]butyl)azetidine-3-sulfonamideformic acid as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.07 (s,1H), 9.45 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.14 (s, 0.5H, FA), 7.87 (s,1H), 7.59-7.52 (m, 2H), 7.13 (s, 1H), 6.94 (s, 1H), 6.84 (d, J=8.6 Hz,1H), 6.78 (s, 2H), 6.55 (s, 1H), 5.03 (dd, J=12.9, 5.4 Hz, 1H), 3.84 (s,7H), 3.60 (s, 4H), 3.28-3.20 (m, 3H), 3.16 (d, J=6.3 Hz, 3H), 2.97 (d,J=6.5 Hz, 2H), 2.92-2.81 (m, 1H), 2.61-2.53 (m, 3H), 2.03-1.95 (m, 1H),1.55 (s, 4H). LCMS (ESI) m/z: [M+H]⁺=772.30.

Example 29—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl)azetidine-3-sulfonamide formic acid (Compound D23 Formic Acid)

Step 1: Preparation oftert-butyl-3-[(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]pentyl)sulfamoyl]azetidine-1-carboxylate (i28-2)

To a stirred mixture of5-[(5-aminopentyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(100.00 mg, 0.279 mmol, 1.00 equiv) and tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate (178.37 mg, 0.698 mmol, 2.50equiv) in DCM (2.00 mL) was added TEA (84.70 mg, 0.837 mmol, 3.00equiv). After stirring for 1.5 hours at room temperature, the resultingmixture was concentrated under reduced pressure. The residue waspurified by Prep-TLC (CH₂Cl₂/EA (1:2)) to affordtert-butyl-3-[(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]pentyl)sulfamoyl]azetidine-1-carboxylate(58.7 mg, 33.87%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=578.

Step 2: Preparation ofN-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)azetidine-3-sulfonamide(i28-3)

To a stirred mixture of tert-butyl3-[(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]pentyl)sulfamoyl]azetidine-1-carboxylate(58.70 mg, 0.102 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (0.40mL, 5.385 mmol, 52.99 equiv). After stirring for 1 hour at roomtemperature, the resulting mixture was concentrated under reducedpressure. The residue was used in the next step directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=478.17.

Step 3: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl)azetidine-3-sulfonamideformic acid (Compound D22 Formic Acid)

A mixture ofN-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl)azetidine-3-sulfonamide (48.54 mg, 0.102 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(39.56 mg, 0.122 mmol, 1.20 equiv) in THF (2 mL) was stirred at roomtemperature, then adjusted to pH 8-˜9 with TEA. To the above mixture wasadded NaBH₃CN (12.78 mg, 0.203 mmol, 2.00 equiv) in portions, and theresulting mixture was stirred for 2 hours at room temperature. Theresulting mixture was concentrated under reduced pressure, and theresidue was purified by Prep-HPLC (conditions: Sun Fire C18 OBD PrepColumn, 19 mm×250 mm; mobile phase, Water (0.1% FA) and ACN (hold 3%Phase B in 2 minutes, up to 15% in 8 minutes); Detector, UV). Thisresulted in 7.4 mg (8.31%) of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]pentyl)azetidine-3-sulfonamideformic acid as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.07 (s,1H), 9.44 (s, 1H), 8.72 (d, J=5.7 Hz, 1H), 7.86 (s, 1H), 7.59-7.52 (m,2H), 7.21 (s, 1H), 7.11 (s, 1H), 6.93 (s, 1H), 6.83 (dd, J=8.3, 1.7 Hz,1H), 6.76 (s, 2H), 6.55 (s, 1H), 5.03 (dd, J=13.0, 5.4 Hz, 1H), 4.02 (s,1H), 3.83 (s, 6H), 3.60 (s, 4H), 3.29-3.20 (m, 2H), 3.19-3.08 (m, 3H),3.01-2.78 (m, 4H), 2.61-2.51 (m, 3H), 2.06-1.93 (t, J=12.7 Hz, 1H),1.60-1.51 (m, 2H), 1.50-1.42 (m, 2H), 1.42-1.32 (m, 2H). LCMS (ESI) m/z:[M+H]⁺=786.28.

Example 30—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamideformic acid (Compound D24 Formic Acid)

Step 1: Preparation of tert-butylN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)carbamate(i30-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430mmol, 1.00 equiv) and tert-butyl N-[2-(piperazin-1-yl)ethyl]carbamate(1.49 g, 6.516 mmol, 1.20 equiv) in NMP (10.00 mL) was added DIEA (1.40g, 10.861 mmol, 2.00 equiv) dropwise at room temperature. The resultingmixture was stirred for 6 hours at 90° C. under nitrogen atmosphere. Theresidue was purified by reverse flash chromatography (conditions:column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradientin 20 minutes; detector, UV 254 nm). This resulted in tert-butylN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)carbamate(2 g, 75.85%) as a green oil. LCMS (ESI) m/z: [M+H]+=486.

Step 2: Preparation of5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(i30-3)

A solution of tert-butylN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)carbamate (2.00 g, 4.119 mmol, 1.00 equiv) and TFA (2.00 mL, 26.926mmol, 6.54 equiv) in DCM (5.00 mL, 78.650 mmol, 19.09 equiv) was stirredfor 1 hours at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(1.5 g, 94.48%) as a green solid. LCMS (ESI) m/z: [M+H]+=386.

Step 3: Preparation of tert-butyl3-[(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)sulfamoyl]azetidine-1-carboxylate(i30-4)

To a stirred solution of5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(400.00 mg, 1.038 mmol, 1.00 equiv) and tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate (318.46 mg, 1.245 mmol, 1.20equiv) in DCM (10.00 mL) was added TEA (210.03 mg, 2.076 mmol, 2.00equiv) at room temperature. The resulting mixture was stirred for 2hours at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by silica gel column chromatography,eluted with DCM/EtOAc (1:1) to afford tert-butyl3-[(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)sulfamoyl]azetidine-1-carboxylate(500 mg, 79.68%) as a green solid. LCMS (ESI) m/z: [M+H]⁺=605.

Step 4: Preparation ofN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide(i30-5)

A solution of tert-butyl3-[(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)sulfamoyl]azetidine-1-carboxylate (500.00 mg, 0.827 mmol, 1.00 equiv)and TFA (3.00 mL) in DCM (5.00 mL) was stirred for 1 hour at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted inN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide(400 mg, 95.87%) as a green solid. LCMS (ESI) m/z: [M+H]⁺=505.

Step 5: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamideformic acid (Compound D24 Formic Acid)

A solution ofN-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide(60.00 mg, 0.119 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(46.28 mg, 0.143 mmol, 1.20 equiv) in DMF (1.50 mL) was stirred for 20minutes at room temperature. Then NaBH₃CN (14.95 mg, 0.238 mmol, 2.00equiv) was added to the reaction mixture. The resulting mixture wasstirred for 1 hour at room temperature. The residue was purified byreverse flash chromatography (conditions: column, C18 silica gel; mobilephase, ACN in water, 10% to 50% gradient in 20 minutes; detector, UV 254nm). This resulted in1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)azetidine-3-sulfonamide(9.4 mg, 9.72%) as a green solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.79(brs, 0.8H, FA(COOH)), 11.08 (s, 1H), 9.44 (s, 1H), 8.71 (d, J=5.7 Hz,1H), 8.14 (s, 0.8H, FA), 7.86 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d,J=5.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.24 (dd, J=8.8, 2.3 Hz, 1H),7.11 (s, 1H), 6.73 (s, 2H), 5.07 (dd, J=13.0, 5.4 Hz, 1H), 4.08-4.02 (m,1H), 3.82 (s, 7H), 3.69-3.62 (m, 2H), 3.60 (s, 3H), 3.50-3.39 (m, 8H),3.12-3.05 (m, 2H), 2.95-2.83 (m, 1H), 2.63-2.55 (m, 3H), 2.55 (s, 2H),2.47-2.39 (m, 3H), 2.07-1.98 (m, 1H). LCMS (ESI) m/z: [M+H]⁺=813.30.

Example 31—Preparation of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethyl)(methyl)amino]ethyl]azetidine-2-carboxamide(Compound D25)

To a solution of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-2-carboxylicacid (80 mg, 0.195 mmol, 1.00 equiv) and DIEA (75.8 mg, 0.586 mmol, 3.00equiv) in DMF (1.50 mL) was added HATU (111.4 mg, 0.293 mmol, 1.50equiv), and the resulting solution was stirred at room temperature for 1hour. The crude mixture was directly purified by Prep-HPLC (conditions:SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A:Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minuteute;Gradient: 7% B to 22% B in 8 minutes; 254 nm; R_(t): 7.75 minutes) toafford(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethyl)(methyl)amino]ethyl]azetidine-2-carboxamide(5.5 mg, 3.5%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.45(d, J=1.1 Hz, 1H), 8.67 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=5.9Hz, 1H), 7.54-7.42 (m, 1H), 6.99 (d, J=7.1 Hz, 1H), 6.91 (dd, J=8.5, 3.1Hz, 1H), 6.71 (d, J=0.9 Hz, 2H), 5.13-5.02 (m, 1H), 3.86 (s, 8H), 3.66(d, J=1.0 Hz, 5H), 3.28 (s, 5H), 2.76-2.66 (m, 6H), 2.53-2.42 (m, 2H),2.34 (s, 3H), 2.30-2.19 (m, 1H), 2.15-1.94 (m, 2H). LCMS (ESI) m/z:[M+H]+=765.30.

Example 32—Preparation ofN-[2-[(2-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]formamido]ethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]acetamide(Compound D26)

To a solution of(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-2-carboxylicacid (30 mg, 0.073 mmol, 1.00 equiv) and DIEA (28.4 mg, 0.220 mmol, 3.00equiv) in DMF (1.00 mL) was added HATU (41.8 mg, 0.110 mmol, 1.50 equiv)andN-[2-[(2-aminoethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]acetamide(31.61 mg, 0.073 mmol, 1.00 equiv). The resulting solution was stirredat room temperature for 1 hour. The crude mixture was directly purifiedby Prep-HPLC (condition: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minuteute; Gradient: 5% B to 5% B in 2 minutes; 254 nm;R_(t): 9.88 minutes) to affordN-[2-[(2-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]formamido]ethyl)(methyl)amino]ethyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy]acetamide(4.8 mg, 7.5%) as a yellow solid. ¹H NMR (300 MHz, Acetonitrile-d3) δ9.52 (s, 1H), 9.11 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.20-8.02 (m, 1H),7.79 (t, J=6.5 Hz, 2H), 7.57 (d, J=5.0 Hz, 2H), 7.45-7.23 (m, 2H), 6.73(s, 2H), 4.99 (dd, J=12.1, 5.3 Hz, 1H), 4.63 (s, 2H), 4.38 (s, 1H), 4.11(s, 2H), 3.87 (s, 6H), 3.72-3.60 (m, 5H), 3.59-3.49 (m, 2H), 3.45 (d,J=5.6 Hz, 2H), 3.01 (dt, J=11.1, 5.7 Hz, 4H), 2.83-2.72 (m, 2H),2.72-2.60 (m, 5H), 2.13 (ddd, J=10.6, 5.5, 3.1 Hz, 2H). LCMS (ESI) m/z:[M+H]+=823.45.

Example 33—Preparation of4-(((((S)-1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D27)

Step 1: Preparation of tert-butyl(2S)-2-((2,2,2-trifluoroacetamido)methyl)azetidine-1-carboxylate (i33-2)

To a solution of tert-butyl (2S)-2-(aminomethyl)azetidine-1-carboxylate(900.00 mg, 4.832 mmol, 1.00 equiv) and trifluoroacetic anhydride(1522.33 mg, 7.248 mmol, 1.5 equiv) in THF (9.00 mL) was added TEA(977.92 mg, 9.664 mmol, 2 equiv). The mixture was stirred at 25° C. for12 hours. The resulting solution was diluted with EA. Then washed withwater (3×50 mL). The residue was applied onto a silica gel column withethyl EA/PE (15/85). The resulting mixture were evaporated to dryness toafford tert-butyl (2S)-2-[(2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate (1270 mg, 93.11%) as a yellow oil. LCMS(ESI) m/z: [M+H]+=283.

Step 2: Preparation of tert-butyl(2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate(i33-3)

To a solution of tert-butyl(2S)-2-[(2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate(1270.00 mg, 4.499 mmol, 1.00 equiv) and dimethyl sulfate (681.00 mg,5.399 mmol, 1.2 equiv) in acetone (15.00 mL) was added K₂CO₃ (621.83 mg,4.499 mmol, 1 equiv). The mixture was stirred at 25° C. for 12 hours.The resulting mixture were evaporated to dryness to afford tert-butyl(2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate(1640 mg, 123.02%) as a yellow oil that was used directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=297.

Step 3: Preparation ofN-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide (i33-4)

A solution of tert-butyl(2S)-2-[(2,2,2-trifluoro-N-methylacetamido)methyl]azetidine-1-carboxylate(1.64 g, 5.535 mmol, 1.00 equiv) and TFA (3.50 mL, 47.121 mmol, 8.51equiv) in DCM (16.00 mL) was stirred for 1 hour at 25° C. The mixturewas concentrated to giveN-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide (2.08 g)as a brown oil that was used directly without further purification. LCMS(ESI) m/z: [M+H]+=197.

Step 4: Preparation ofN-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide(33-5)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(552.00 mg, 1.702 mmol, 1.00 equiv) andN-[(2S)-azetidin-2-ylmethyl]-2,2,2-trifluoro-N-methylacetamide(500.81mg, 2.553 mmol, 1.50 equiv) in DMF (6.00 mL) was added NaBH(OAc)₃(721.42 mg, 3.404 mmol, 2.00 equiv). The resulting solution was stirredat 25° C. for 1 hour. The mixture was concentrated to give crude productthat was purified by chromatography on silica gel eluted with MeOH/DCM(5:95) to giveN-[[(2S)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide(275 mg, 32.03%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=505.

Step 5: Preparation of(S)-4-(3,5-dimethoxy-4-((2-((methylamino)methyl)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i33-6)

A solution ofN-[[(2R)-1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-2-yl]methyl]-2,2,2-trifluoro-N-methylacetamide(230 mg, 0.456 mmol, 1.00 equiv) and NH₃·H₂O (1 mL, 0.008 mmol, 0.05equiv) in DMF (2.50 mL) was stirred at 25° C. for 1 hour. The resultingmixture were evaporated to dryness to afford4-(3,5-dimethoxy-4-[[(2R)-2-[(methylamino)methyl]azetidin-1-yl]methyl]phenyl)-2-methyl-2,7-naphthyridin-1-one (219mg) as a brown oil that was used directly without further purification.LCMS (ESI) m/z: [M+H]+=409.

Step 6: Preparation of4-(((((S)-1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D27)

To a stirred solution of4-(3,5-dimethoxy-4-[[(2R)-2-[(methylamino)methyl]azetidin-1-yl]methyl]phenyl)-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(150.00 mg, 0.367 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carbaldehyde(105.11 mg, 0.367 mmol, 1.00 equiv) in MeOH (2.00 mL) was added NaBH₃CN(115.38 mg, 1.836 mmol, 5 equiv). The mixture was stirred at 25° C. for1 hour. Without any additional work-up, the mixture was purified byprep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 3% B to 3% B in 2 minutes; 254 nm; Rt:14.55 minutes) to give4-(((((S)-1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-2-yl)methyl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(8.0 mg, 3.01%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.54(s, 1H), 8.67 (d, J=5.7 Hz, 1H), 8.57 (s, 0.4H, FA), 7.91-7.86 (m, 1H),7.84 (d, J=6.0 Hz, 2H), 7.74 (d, J=6.5 Hz, 1H), 7.57 (t, J=6.3 Hz, 1H),6.84 (d, J=5.4 Hz, 2H), 5.20-5.08 (m, 1H), 4.72-4.31 (m, 3H), 4.15-3.98(m, 3H), 3.92 (d, J=11.5 Hz, 6H), 3.71 (d, J=1.8 Hz, 3H), 2.99-2.80 (m,3H), 2.80-2.49 (m, 4H), 2.38-1.98 (m, 5H). LCMS (ESI) m/z:[M+H]+=679.30.

Example 34—Preparation of4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D28)

Step 1: Preparation of tert-butyl(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl)carbamate(i34-2)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde (250.00 mg, 0.772 mmol, 1.00 equiv) and tert-butylazetidin-3-yl(methyl) carbamate hydrochloride (171.38 mg, 0.772 mmol,1.00 equiv), was added Et₃N (77.97 mg, 0.772 mmol, 1.00 equiv) andNaBH₃CN (97.27 mg, 1.544 mmol, 2.00 equiv). The resulting mixture wasstirred overnight. The mixture was concentrated under vacuum. Theresidue was purified by silica gel column chromatography, eluted with EAin PE from 0% to 40% to afford tert-butyl(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl)carbamate (170 mg, 0.344 mmol, 44.62%) as a white solid. LCMS (ESI) m/z:[M+H]⁺=495.

Step 2: Preparation of4-(3,5-dimethoxy-4-((3-(methylamino)azetidin-1-y)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i34-3)

Tert-butyl(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl) (methyl) carbamate (170 mg, 0.344 mmol, 1.00 equiv) wasdissolved in 4 N HCl in 1,4-dioxane (5 mL, 20 mmol, 58.13 equiv). Theresulting solution was stirred for one hour at room temperature. Theresulting mixture was concentrated to afford4-(3,5-dimethoxy-4-((3-(methylamino)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(180 mg, crude) as a white solid, that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=395.

Step 3: Preparation of4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)(methyl)amino)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D28)

To a mixture of4-(3,5-dimethoxy-4-[[3-(methylamino)azetidin-1-yl]methyl]phenyl)-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(30.00 mg, 0.076 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carbaldehyde(21.77 mg, 0.076 mmol, 1.00 equiv) in MeOH (2.00 mL) was added AcOH(0.05 mg, 0.001 mmol, 0.01 equiv). The mixture was stirred for 1 hour.NaBH₃CN (9.56 mg, 0.152 mmol, 2.00 equiv) was added. The resultingmixture was stirred for 1 hour. The crude product was purified bypreparative HPLC (condition: SunFire C₁₈ OBD Prep Column, 100 Å, 5 μm,19 mm×250 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN;Flow rate: 25 mL/minuteute; Gradient: 5% B to 5% B in 2 minutes; 254 nm;R_(t): 12.63 minutes. This afforded4-[[(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]azetidin-3-yl)(methyl)amino]methyl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(18.90 mg, 0.028 mmol, 36.53%) as a light yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.60 (s, 1H), 8.70 (d, J=6.3 Hz, 1H), 8.00 (s, 1H),7.96-7.82 (m, 4H), 6.88 (s, 2H), 5.17 (dd, J=12.4, 5.4 Hz, 1H), 4.58 (s,2H), 4.33 (t, J=7.2 Hz, 4H), 4.10 (d, J=13.2 Hz, 1H), 4.02 (d, J=13.2Hz, 1H), 3.97 (s, 6H), 3.75 (s, 4H), 2.95-2.83 (m, 1H), 2.81-2.67 (m,2H), 2.29 (s, 3H), 2.21-2.11 (m, 1H). LCMS (ESI) m/z: [M+H]⁺=665.30.

Example 35—Preparation of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-3-carboxamide(Compound D29)

Step 1: Preparation of2-(2,6-dioxopiperidin-3-yl)-4-((methylamino)methyl)isoindoline-1,3-dione(i35-2)

To a solution of2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-carbaldehyde (70.00mg, 0.245 mmol, 1.00 equiv) in DMF (3.00 mL) was added methanaminehydrochloride (24.77 mg, 0.367 mmol, 1.50 equiv). The resulting mixturewas stirred overnight at room temperature. Then NaBH(OAc)₃ (103.88 mg,0.490 mmol, 2.00 equiv) was added. The resulting mixture was stirred for1 hour at room temperature. The resulting mixture was purified byreverse phase column with ACN in water from (0% to 50%) to afford2-(2,6-dioxopiperidin-3-yl)-4-((methylamino)methyl)isoindoline-1,3-dione(30 mg, 41.10%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=302.

Step 2: Preparation of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-3-carboxamide(Compound D29)

To a mixture of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidine-3-carboxylicacid (40.77 mg, 0.100 mmol, 1.00 equiv) in DMF (3.00 mL) was added HATU(94.65 mg, 0.250 mmol, 2.50 equiv) and DIEA (38.61 mg, 0.300 mmol, 3.00equiv). The resulting mixture was stirred for 2 hours at roomtemperature. Then2-(2,6-dioxopiperidin-3-yl)-4-((methylamino)methyl)isoindoline-1,3-dione(30.00 mg, 0.100 mmol, 1.00 equiv) was added. The resulting mixture wasstirred for 1 hour. The crude product was purified by preparative HPLC(conditions: XSelect CSH Prep C₁₈ OBD Column, 5 μm, 19*150 mm; MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minuteute; Gradient: 12% B to 12% B in 2 minutes; 254/220 nm; R_(t):13.57 min Fractions containing the desired compound were evaporated todryness to afford1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N-methylazetidine-3-carboxamide(17.10 mg, 24.25%) as a light yellow solid. ¹H-NMR (400 MHz,Methanol-d4) δ 9.58 (s, 1H), 8.69 (t, J=7.8 Hz, 1H), 7.98-7.87 (m, 2H),7.85-7.77 (m, 2H), 7.72-7.64 (m, 1H), 6.89 (d, J=8.2 Hz, 2H), 5.22-5.01(m, 3H), 4.65-4.36 (m, 5H), 4.34-4.21 (m, 1H), 4.20-4.07 (m, 1H),4.01-3.92 (m, 6H), 3.74 (s, 3H), 3.02 (s, 3H), 2.96-2.84 (m, 1H),2.80-2.71 (m, 2H), 2.24-2.12 (m, 1H). LCMS (ESI) m/z: [M+H]⁺=693.35.

Example 36—Preparation of1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)sulfonyl)ethyl)azetidine-3-carboxamide(Compound D30)

Into a stirred mixture of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]azetidine-3-carboxylicacid (53.00 mg, 0.129 mmol, 1.00 equiv) and DIEA (N,N-diisopropylamine)(50.19 mg, 0.388 mmol, 3.00 equiv) in DMF (dimethylformamide) (1.00 mL)was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate,N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU) (73.83 mg, 0.194 mmol, 1.50 equiv) at0° C. After 10 minutes, to the above mixture was added4-[[2-(2-aminoethanesulfonyl)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (63.44 mg,0.155 mmol, 1.20 equiv). Then the reaction was stirred at roomtemperature for 2 hours under N₂ atmosphere. The crude product waspurified by Prep-HPLC (conditions: Sunfire C18 OBD Prep Column, 5 μm, 19mm*250 mm; Mobile Phase A: Water (0.05% TFA, trifluoroacetic acid),Mobile Phase B: acetonitrile (MeCN or ACN); Flow rate: 25 mL/minuteute;Gradient: 3% B to 3% B in 2 minutes; 254 nm; R_(t): 13.98 minutes). Thisresulted in1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)sulfonyl)ethyl)azetidine-3-carboxamide18.4 mg (16.47%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.52(d, J=0.8 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (br s, 0.5H, FA), 7.77(s, 1H), 7.67-7.55 (m, 2H), 7.13 (t, J=7.6 Hz, 2H), 6.83 (s, 2H), 5.06(dd, J=12.3, 5.4 Hz, 1H), 4.37 (s, 2H), 4.23-4.06 (m, 4H), 3.95 (s, 6H),3.89 (t, J=6.3 Hz, 2H), 3.77-3.69 (m, 2H), 3.71 (s, 3H), 3.52 (q, J=6.9,6.3 Hz, 3H), 3.38 (t, J=6.3 Hz, 2H), 2.62-2.93 (m, 3H), 2.07-2.17 (m,1H). LCMS (ESI) m/z: [M+H]⁺=800.35.

Example 37—Preparation of5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D31 Formic Acid)

Step 1: Preparation of tert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidine-1-carboxylate(i37-2)

To a mixture of tert-butyl 3-bromoazetidine-1-carboxylate (2.00 g, 8.511mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (2.33 g,8.511 mmol, 1.00 equiv) in DMF (30.00 mL) was added Cs₂CO₃ (5.53 g,17.022 mmol, 2.00 equiv). The resulting mixture was stirred overnight at90° C. The resulting mixture was concentrated under vacuum. The residuewas purified by silica gel column chromatography, eluted with EA in PEfrom 0% to 50% to afford tert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidine-1-carboxylate(400 mg, 10.96%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=430.

Step 2: Preparation of5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(i37-3)

To a solution of tert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidine-1-carboxylate(400.00 mg, 0.932 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added HCl(4 N in 1,4-dioxane) (5 mL, 20.000 mmol, 21.46 equiv). The resultingsolution was stirred for 1 hour at room temperature. The resultingmixture was concentrated under vacuum to afford5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(440.00 mg, crude) as a white solid. LCMS (ESI) m/z: [M+H]⁺=330.

Step 3: Preparation of tert-butyl(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)zetidin-1-yl)propyl)carbamate (i37-4)

A mixture of5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(200.00 mg, 0.608 mmol, 1.00 equiv) and tert-butyl(3-oxopropyl)carbamate (105.18 mg, 0.608 mmol, 1.00 equiv) in MeOH (5.00mL) was stirred for 1.5 hours at room temperature. Then NaBH₃CN (75.39mg, 1.216 mmol, 2.00 equiv) was added. The resulting mixture was stirredfor 1 hour at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified by silica gel columnchromatograpy, eluted with EA in PE from 0% to 50% to afford tert-butyl(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)zetidin-1-yl)propyl)carbamate(100.00 mg, 33.89%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=487.

Step 4: Preparation of5-((1-(3-aminopropyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i37-5)

To a solution of tert-butyl(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl)carbamate (100.00 mg, 0.206 mmol, 1.00 equiv) inDCM (4.00 mL) was added TFA (4.00 mL, 53.860 mmol, 261.46 equiv). Theresulting mixture was stirred for one hour at room temperature. Theresulting mixture was concentrated under vacuum to afford5-((1-(3-aminopropyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(120 mg, crude). LCMS (ESI) m/z: [M+H]+=387.

Step 5: Preparation of5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D31 Formic Acid)

To a solution of5-((1-(3-aminopropyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(60.00 mg, 0.155 mmol, 1.00 equiv) in MeOH (5.00 mL, 123.495 mmol,795.32 equiv) was added2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(50.36 mg, 0.155 mmol, 1 equiv). The resulting mixture was stirred for 1hour. Then NaBH₃CN (19.52 mg, 0.311 mmol, 2 equiv) was added. Theresulting mixture was stirred for 1 hour. The resulting mixture wasfiltered, and the filtrate was purified by prep-HPLC (conditions:SunFire C₁₈ OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A:Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient:5% B to 5% B in 2 minutes; 254 nm; Rt: 9.75 minutes) to afford5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;formate (14.4 mg, 12.52%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.52 (s, 1H), 8.67 (d, J=5.7 Hz, 1H), 8.26 (br s, 0.65H,FA), 7.82-7.75 (m, 2H), 7.60 (dd, J=5.8, 0.9 Hz, 1H), 7.21 (dq, J=4.6,2.3 Hz, 2H), 6.88 (s, 2H), 5.13-5.00 (m, 2H), 4.36 (s, 2H), 3.99 (s,6H), 3.93-3.89 (m, 2H), 3.71 (s, 3H), 3.44 (d, J=8.2 Hz, 2H), 3.22 (t,J=6.7 Hz, 2H), 2.95-2.82 (m, 3H), 2.82-2.62 (m, 2H), 2.21-2.05 (m, 1H),1.89-1.81 (m, 2H). LCMS (ESI) m/z: [M+H]⁺=695.40.

Example 38—Preparation of4-(4-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D32)

Step 1: Preparation of tert-butyl6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(i38-2)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(700.00mg, 2.158 mmol, 1.00 equiv) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (427.91 mg, 2.158 mmol, 1.00equiv) in DMF (10.00 mL, 129.218 mmol, 59.87 equiv) was added NaBH(OAc)₃(914.85 mg, 4.317 mmol, 2.00 equiv). The resulting solution was stirredat 25° C. for 1 hour. The mixture was concentrated to give crude productthat was purified by chromatography on silica gel eluted with MeOH/DCM(6:94) to givetert-butyl6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3] heptane-2-carboxylate(808 mg, 73.90%) as an off-white solid. LCMS(ESI) m/z: [M+H]+=507.

Step 2: Preparation of4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i38-3)

A solution of tert-butyl6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (708.00 mg, 1.398 mmol,1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 14.45 equiv) in DCM (7.00 mL,110.110 mmol, 78.79 equiv) was stirred at 25° C. for 1 hour. The mixturewas concentrated to give crude product 4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(696 mg) as a brown oil that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=407.

Step 3: Preparation of4-(4-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D32)

To a solution of4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(40.00 mg, 0.098 mmol, 1.00 equiv) and4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid(35.46 mg, 0.098 mmol, 1.00 equiv) in DMF (1.0 mL) was added HATU (56.12mg, 0.148 mmol, 1.5 equiv) and DIEA (31.80 mg, 0.246 mmol, 10 equiv).The mixture was stirred at 25° C. for 1 hour. The mixture was purifiedby prep-HPLC (conditions: Kinetex EVO C18 Column 21.2*150, 5 μm; MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute;Gradient: 16% B to 26% B in 8 minutes; 254/220 nm; Rt: 7.03 minutes) toafford4-[4-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(12 mg, 16.29%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.53(s, 1H), 8.70 (d, J=5.8 Hz, 1H), 7.79 (dd, J=8.5, 7.4 Hz, 1H), 7.78 (s,1H), 7.62 (d, J=5.8 Hz, 1H), 7.46 (dd, J=14.7, 7.9 Hz, 2H), 6.86 (s,2H), 5.13 (dd, J=12.5, 5.4 Hz, 1H), 4.60 (s, 1H), 4.40 (d, J=13.7 Hz,4H), 4.32-4.19 (m, 6H), 4.14 (s, 2H), 3.96 (s, 6H), 3.71 (s, 3H),2.95-2.68 (m, 3H), 2.53-2.34 (m, 2H), 2.20-2.10 (m, 3H). LCMS (ESI) m/z:[M+H]+=749.40.

Example 39—Preparation of4-(4-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D33)

To a stirred mixture of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(50.00 mg, 0.127 mmol, 1.00 equiv) and4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid(45.67 mg, 0.127 mmol, 1.00 equiv) in DMF (2.00 mL) was added DIEA(163.82 mg, 1.268 mmol, 10.00 equiv) and HATU (96.39 mg, 0.254 mmol,2.00 equiv) at 0° C. The above mixture was stirred for 3 hours at roomtemperature. Then the crude product was purified by preparative HPLC(conditions: XBridge Shield RP18 OBD Column, 5 μm, 19*250 mm; MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute;Gradient: 12% B to 26% B in 8 minutes; 254 nm; Rt: 7.91 minutes). Thisresulted in4-(4-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-4-oxobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(5.60 mg, 5.54%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.54(s, 1H), 8.69 (d, J=5.8 Hz, 1H), 7.85-7.73 (m, 2H), 7.63 (d, J=5.7 Hz,1H), 7.52-7.43 (m, 2H), 6.79 (s, 2H), 5.11 (dd, J=12.2, 5.4 Hz, 1H),4.30 (t, J=5.8 Hz, 2H), 4.01 (s, 2H), 3.90 (s, 6H), 3.81-3.65 (m, 7H),2.98-2.81 (m, 6H), 2.79-2.67 (m, 3H), 2.24-2.07 (m, 3H). vLCMS (ESI)m/z: [M+H]⁺=737.40.

Example 40—Preparation of4-((5-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D34)

Step 1: Preparation of tert-butyl6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(i40-2)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(700.00 mg, 2.158 mmol, 1.00 equiv) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (427.91 mg, 2.158 mmol, 1.00equiv) in DMF (10.00 mL, 129.218 mmol, 59.87 equiv) was added NaBH(OAc)₃(914.85 mg, 4.317 mmol, 2.00 equiv). The resulting solution was stirredat 25° C. for 1 hour. The mixture was concentrated to give crude productthat was purified by chromatography on silica gel eluted with MeOH]/DCM(6:94) to give tert-butyl6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(808mg, 73.90%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=507.

Step 2: Preparation of4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i40-3)

A solution of tert-butyl6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(708.00 mg, 1.398 mmol, 1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 14.45equiv) in DCM (7 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated to give crude product4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(696 mg) as a brown oil that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=407.

Step 3: Preparation of4-((5-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D34)

To a solution of4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(40.00 mg, 0.098 mmol, 1.00 equiv) and5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoicacid (36.84 mg, 0.098 mmol, 1 equiv) in DMF (1 mL) was added HATU (56.12mg, 0.148 mmol, 1.5 equiv) and DIEA (31.80 mg, 0.246 mmol, 10 equiv).The mixture was stirred at 25° C. for 1 hour. The mixture was purifiedby prep-HPLC (conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 12% B to 22% B in 12 minutes; 254/220 nm; Rt: 10.52minutes) to afford4-[[5-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(10.1 mg, 13.46%) as a light yellow solid.

¹H NMR (400 MHz, Methanol-d4) δ 9.58 (s, 1H), 8.73-8.67 (m, 1H), 7.92(d, J=6.9 Hz, 1H), 7.84-7.76 (m, 1H), 7.47 (t, J=8.1 Hz, 2H), 6.89 (d,J=3.5 Hz, 2H), 5.17-5.07 (m, 1H), 4.51 (d, J=3.0 Hz, 2H), 4.45-4.31 (m,6H), 4.27 (t, J=5.5 Hz, 2H), 4.19 (s, 1H), 4.12 (s, 1H), 3.98 (d, J=3.4Hz, 6H), 3.74 (d, J=1.7 Hz, 3H), 2.96-2.65 (m, 3H), 2.34-2.30 (m, 2H),2.19-2.12 (m, 1H), 1.96-1.89 (m, 2H), 1.88-1.80 (m, 2H). LCMS (ESI) m/z:[M+H]+=763.40.

Example 41—Preparation of4-((5-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-5-oxopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D35 Formic Acid)

To a stirred solution of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(50.0 mg, 0.127 mmol, 1.00 equiv) and5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoicacid (47.5 mg, 0.127 mmol, 1.00 equiv) in DMF (1 mL) was added DIEA(163.8 mg, 1.268 mmol, 10.00 equiv) dropwise at room temperature. Theresulting mixture was stirred for 10 min at room temperature. To theabove mixture was added HATU (96.4 mg, 0.254 mmol, 2.00 equiv). Theresulting mixture was stirred for additional 2 hours at roomtemperature. The residue was purified by reverse flash chromatography(conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 9 B to 27 B in 10 minutes; 254 nm; R_(T): 10.12) toafford4-[[5-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(6.6 mg, 6.7%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.53(d, J=0.9 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.45 (br s, 0.13H, FA),7.81-7.73 (m, 2H), 7.64 (dd, J=5.8, 0.9 Hz, 1H), 7.45 (dd, J=7.9, 6.2Hz, 2H), 6.79 (s, 2H), 5.11 (dd, J=12.5, 5.5 Hz, 1H), 4.28 (t, J=5.7 Hz,2H), 3.97 (s, 2H), 3.90 (s, 6H), 3.74-3.62 (m, 7H), 2.95-2.81 (m, 3H),2.80-2.65 (m, 4H), 2.60 (t, J=7.4 Hz, 2H), 2.17-2.07 (m, 1H), 1.99-1.83(m, 4H). LCMS (ESI) m/z: [M+H]+=751.40

Example 42—Preparation of4-(2-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D36 Formic Acid)

Step 1: Preparation of tert-butyl6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(i42-2)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(700.00 mg, 2.158 mmol, 1.00 equiv) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (427.91 mg, 2.158 mmol, 1.00equiv) in DMF (10 mL) was added NaBH(OAc)₃ (914.85 mg, 4.317 mmol, 2.00equiv). The resulting solution was stirred at 25° C. for 1 hour. Themixture was concentrated to give crude product that was purified bychromatography on silica gel eluted with MeOH]/DCM (6:94) to givetert-butyl6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(808 mg, 73.90%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=507.

Step 2: Preparation of4-(4-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i42-3)

To a solution of tert-butyl6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(708.00 mg, 1.398 mmol, 1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 14.45equiv) in DCM (7 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated to give crude product4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(696 mg) as a brown oil that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=407.

Step 3: Preparation of4-(2-(6-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-y)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D35 Formic Acid)

To a solution of4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(40.00 mg, 0.098 mmol, 1.00 equiv) and[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(32.70 mg, 0.098 mmol, 1.00 equiv) in DMF (1 mL) was added HATU (56.12mg, 0.148 mmol, 1.50 equiv) and DIEA (31.80 mg, 0.246 mmol, 10 equiv).The mixture was stirred at 25° C. for 1 hour. The mixture was purifiedby prep-HPLC (conditions: SunFire Prep C18 OBD Column 19×150 mm 5 μm 10nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 8% B to 21% B in 10 minutes; 254/220 nm; Rt: 8.20minutes) to afford4-[2-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(6.2 mg, 8.74%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.51(s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.55 (br s, 0.46H, FA), 7.80 (s, 1H),7.69 (t, J=8.1 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.44 (dd, J=11.8, 7.2Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.87 (s, 2H), 5.19-5.10 (m, 1H),4.69-4.51 (m, 6H), 4.39 (s, 2H), 4.34-4.26 (m, 2H), 4.22 (s, 2H), 3.97(s, 6H), 3.69 (s, 3H), 2.95-2.68 (m, 3H), 2.20-2.09 (m, 1H). LCMS (ESI)m/z: [M+H]+=721.35.

Example 43—Preparation of4-(2-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D37 Formic Acid)

To a stirred solution of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(50.0 mg, 0.127 mmol, 1.00 equiv) and[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(42.1 mg, 0.127 mmol, 1.00 equiv) in DMF (1 mL) was added DIEA (163.8mg, 1.268 mmol, 10.00 equiv) dropwise at room temperature. The resultingmixture was stirred for 10 minutes at room temperature. To the abovemixture was added HATU (96.4 mg, 0.254 mmol, 2.00 equiv). The resultingmixture was stirred for additional 2 hours at room temperature. Theresidue was purified by reverse flash chromatography (conditions:SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A:Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient:9 B to 27 B in 10 minutes; 254 nm; R_(T): 10.12 minutes) to afford4-[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (12.2 mg, 13.6%) as a white solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.34 (br s, 0.28H,FA), 7.83-7.73 (m, 2H), 7.67-7.61 (m, 1H), 7.52 (d, J=7.1 Hz, 1H), 7.40(d, J=8.5 Hz, 1H), 6.81 (s, 2H), 5.15-5.09 (m, 3H), 4.08 (s, 2H), 3.92(s, 6H), 3.83-3.73 (m, 4H), 3.72 (s, 3H), 3.05-2.96 (m, 2H), 2.96-2.80(m, 3H), 2.77-2.69 (m, 2H), 2.17-2.11 (m, 1H). LCMS (ESI) m/z:[M+H]+=709.35.

Example 44—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamideformic acid (Compound D38 Formic Acid)

Step 1: Preparation of tert-butylN-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]carbamate(i44-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione(1.0 g, 3.620 mmol, 1.00 equiv) in NMP (15.00 mL) was added DIEA (940.47mg, 7.277 mmol, 2.01 equiv) and tert-butylN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (988.89 mg, 3.982 mmol,1.10 equiv) in portions at room temperature. The resulting solution wasstirred for 12 hours at 90° C. The resulting mixture was washed withwater (3×100 mL). The resulting solution was extracted with ethylacetate (3×200 mL). The organic layers combined and concentrated. Thisresulted in tert-butylN-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]carbamate(1.2 g, 65.70%) as light yellow oil. LCMS (ESI) m/z: [M+H]+=505.

Step 2: Preparation of4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(i44-3)

To a stirred solution of tert-butylN-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4yl]amino]ethoxy)ethoxy]ethyl]carbamate(1.2 g, 2.378 mmol, 1.00 equiv) in DCM (40 mL) was added TFA (10 mL) inportions at room temperature. The resulting solution was stirred for 4hours at room temperature. The resulting mixture was concentrated. Thisresulted in4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(0.8 g, 83.17%) as light yellow oil. LCMS (ESI) m/z: [M+H]+=405.

Step 3: Preparation of tert-butyl3-([2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]sulfamoyl)azetidine-1-carboxylate(i44-4)

To a stirred solution of4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(238.00 mg, 0.588 mmol, 1.00 equiv) in DCM was added TEA (120.00 mg,1.186 mmol, 2.02 equiv) in portions at room temperature. To the abovemixture was added tert-butyl 3-(chlorosulfonyl) azetidine-1-carboxylate(150.00 mg, 0.587 mmol, 1.00 equiv) in portions. The resulting mixturewas stirred for additional 2 hours at room temperature. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/EtOAc(1:1) to afford tert-butyl3-([2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]sulfamoyl)azetidine-1-carboxylate (130 mg, 35.42%) as a lightyellow oil. LCMS (ESI) m/z: [M+H]+=624.

Step 4: Preparation ofN-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethox-y)ethyl)azetidine-3-sulfonamide(i44-5)

To a stirred solution/mixture of tert-butyl3-([2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]sulfamoyl)azetidine-1-carboxylate(120.00 mg, 0.192 mmol, 1.00 equiv) in DCM (4 mL) was added TFA (1 mL)in portions at room temperature. The resulting mixture was stirred for 1hour at room temperature. The resulting mixture was concentrated underreduced pressure. The crude product 130 mg was used in the next stepdirectly without further purification. LCMS (ESI) m/z: [M+H]+=524.

Step 5: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamideformic acid (Compound D38 Formic Acid)

To a stirred solution ofN-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamide (60.00 mg, 0.115 mmol, 1.00 equiv)and 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(74.34 mg, 0.229 mmol, 2.00 equiv) in MeOH was added NaBH(OAc)₃ (97.15mg, 0.458 mmol, 4.00 equiv) in portions at room temperature. Theresulting mixture was stirred for 12 hours at room temperature. Thecrude product was purified by Prep-HPLC (conditions: SunFire Prep C18OBD Column, 19*150 mm 5 μm 10 nm; mobile phase, Water (0.1% FA) and ACN(10% Phase B up to 27% in 8 minutes); Detector, UV). This resulted in1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-[2-(2[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]azetidine-3-sulfonamideformic acid (8.1 mg, 8.05%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.49 (d, J=0.9 Hz, 1H), 8.66 (d, J=5.8 Hz, 1H), 8.45 (brs, 1H, FA), 7.74 (s, 1H), 7.62 (dd, J=5.8, 0.9 Hz, 1H), 7.50 (dd, J=8.5,7.1 Hz, 1H), 7.02 (dd, J=7.8, 5.3 Hz, 2H), 6.79 (s, 2H), 5.07 (dd,J=12.4, 5.4 Hz, 1H), 4.61 (s, 1H), 4.36-4.23 (m, 1H), 4.20 (s, 2H),4.13-3.99 (m, 4H), 3.92 (s, 6H), 3.73-3.64 (m, 9H), 3.55 (t, J=5.1 Hz,2H), 3.50-3.41 (m, 2H), 3.28 (t, J=5.1 Hz, 2H), 2.96-2.61 (m, 3H),2.18-2.04 (m, 1H). LCMS (ESI) m/z: [M+H]+=832.45.

Example 45—Preparation of4-[4-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione.(Compound D39)

To a stirred solution of4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7naphthyridin-1-one(20.00 mg, 0.043 mmol, 1.00 equiv) and4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid(15.00 mg, 0.042 mmol, 0.97 equiv) in DMF was added HATU (25.00 mg,0.066 mmol, 1.53 equiv) and DIEA (60.00 mg, 0.464 mmol, 10.78 equiv) inportions at room temperature. The resulting mixture was stirred for 2hours at room temperature. The crude product was purified by Prep-HPLC(conditions: Gemini-NX C18 AXAI Packed, 21.2*150 mm 5 μm; mobile phase,Water (0.1% FA) and ACN (14% Phase B up to 19% in 10 minutes); Detector,UV). This resulted in4-[4-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(5.1 mg, 14.68%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.55(s, 1H), 8.70 (d, J=5.6 Hz, 1H), 7.85-7.75 (m, 2H), 7.63 (d, J=5.8 Hz,1H), 7.57-7.43 (m, 2H), 6.87 (d, J=5.2 Hz, 2H), 5.12 (d, J=11.8 Hz, 1H),4.41 (s, 2H), 4.37-4.27 (m, 2H), 3.96 (d, J=8.2 Hz, 6H), 3.84-3.60 (m,9H), 3.58-3.45 (m, 3H), 2.92-2.69 (m, 5H), 2.26-2.04 (m, 6H), 1.85-1.60(m, 2H). LCMS (ESI) m/z: [M+H]+=807.40.

Example 46—Preparation of4-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D40 Formic Acid)

To a stirred solution of4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one(30.00 mg, 0.065 mmol, 1.00 equiv) and5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoicacid (24.17 mg, 0.065 mmol, 1 equiv) in DMF (1.00 mL) was added DIEA(83.46 mg, 0.646 mmol, 10.00 equiv) and HATU (36.83 mg, 0.097 mmol, 1.50equiv). The resulting solution was stirred at room temperature for 1hour. Without any additional work-up, the mixture was purified byprep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 9% B to 25% B in 10 minutes; 254 nm; Rt:10.95 minutes) to give(4-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-5-oxopentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (8.6 mg, 15.25%) as a white solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.53 (br s, 1H,FA), 7.85-7.74 (m, 2H), 7.62 (dd, J=5.9, 0.9 Hz, 1H), 7.46 (dd, J=7.8,2.3 Hz, 2H), 6.86 (d, J=5.7 Hz, 2H), 5.12 (dd, J=12.3, 5.4 Hz, 1H), 4.39(s, 2H), 4.35-4.25 (m, 3H), 3.96 (s, 6H), 3.83-3.74 (m, 2H), 3.72 (s,3H), 3.67-3.61 (m, 2H), 3.55-3.50 (m, 3H), 3.00-2.51 (m, 6H), 2.20-1.71(m, 10H). LCMS (ESI) m/z: [M+H]+=821.45.

Example 47—Preparation of4-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D41 Formic Acid)

To a solution of4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one(30.00 mg, 0.065 mmol, 1.00 equiv) and[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(21.46 mg, 0.065 mmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA(83.46 mg, 0.646 mmol, 10.00 equiv) and HATU (36.83 mg, 0.097 mmol, 1.50equiv). The resulting solution was stirred at room temperature for 1hour. Without any additional work-up, the mixture was purified byprep-HPLC (conditions: Phenomenex Gemini C6-Phenyl, 21.2*250 mm, 5 μm;Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 7 B to 26 B in 15 minutes; 254 nm; R_(T): 14.62minutes) to give4-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (3.7 mg, 6.80%) as a white solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.54 (d, J=0.8 Hz, 1H), 8.70 (d, J=5.8 Hz, 1H), 8.56 (brs, 1H, FA), 7.86-7.75 (m, 2H), 7.63 (dd, J=5.8, 0.9 Hz, 1H), 7.54 (d,J=7.2 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 6.86 (s, 2H), 5.17-5.07 (m, 3H),4.30 (s, 2H), 3.95 (s, 6H), 3.87-3.75 (m, 2H), 3.72 (s, 3H), 3.68-3.62(m, 2H), 3.54 (s, 2H), 3.23-3.17 (m, 4H), 2.91-2.65 (m, 3H), 2.22-2.02(m, 3H), 1.80 (s, 2H). LCMS (ESI) m/z: [M+H]+=779.40.

Example 48—Preparation of5-(4-(2-(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D42 Formic Acid)

Step 1: Preparation of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate(i42-2)

To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione(1.38 g, 4.996 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate(930.52 mg, 4.996 mmol, 1.00 equiv) in NMP (20 mL) was added DIPEA(1937.08 mg, 14.988 mmol, 3 equiv). The mixture was stirred at 90° C.for 2 hours (under nitrogen atmosphere). The reaction was monitored byLC-MS. The resulting mixture was diluted with water (70 mL) and thenextracted with EA (3×25 mL). The combined organic layers were washedwith water (2×25 mL) and dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure. The resultingmixture was concentrated under vacuum. The residue was purified byreverse flash chromatography (conditions: column, C18 silica gel; mobilephase, 0.5% FA in water, 10% to 90% gradient in 25 minutes; detector, UV220 nm). The fractions were concentrated under reduced pressure affordtert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate(700 mg, 31.67%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=443.

Step 2: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione(i42-3)

A solution of tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxylate(500.00 mg, 1.130 mmol, 1.00 equiv) and TFA (1.50 mL, 20.195 mmol, 17.87equiv) in DCM (5.00 mL) was stirred at 25° C. for 1 hour. The resultingmixture were evaporated to dryness to afford2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (350mg, 90.47%) as a brown solid. LCMS (ESI) m/z: [M+H]+=343

Step 3: Preparation of tert-butyl4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate(i42-5)

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione(200.00 mg, 0.584 mmol, 1.00 equiv) and tert-butyl4-(2-oxoethyl)piperidine-1-carboxylate (132.79 mg, 0.584 mmol, 1 equiv)in DMF (3.00 mL) was added NaBH(OAc)₃ (247.63 mg, 1.168 mmol, 2 equiv).The resulting solution was stirred at 25° C. for 1 hour. The residue waspurified by reverse flash chromatography (conditions: column, C18 silicagel; mobile phase, ACN in water, 10% to 50% gradient in 10 minutes;detector, UV 254 nm) to give tert-butyl4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate(197.5 mg, 61.06%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=554.

Step 4: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione(i42-6)

To a solution of tert-butyl4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidine-1-carboxylate(197.00 mg, 0.356 mmol, 1.00 equiv) and TFA (0.50 mL, 6.732 mmol, 18.92equiv) in DCM (2.00 mL) was stirred at 25° C. for 1 hour. The mixturewas concentrated to give crude product2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(320 mg) as a yellow oil, that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=454.

Step 5: Preparation of5-(4-(2-(1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D42 Formic Acid)

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(100.68 mg, 0.222 mmol, 1.20 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(60.00 mg, 0.185 mmol, 1.00 equiv) in DMF (1.5 mL) was added NaBH(OAc)₃(78.42 mg, 0.370 mmol, 2 equiv). The mixture was stirred at 25° C. for 1hour. The mixture was purified by prep-HPLC (conditions: SunFire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 10 B to 12 B in10 minutes; 254 nm; R_(T): 8.7 minutes) to afford5-[4-[2-(1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperidin-4-yl)ethyl]piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(24 mg, 17.03%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.55(d, J=0.9 Hz, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.15 (br s, 0.2H, FA),7.80-7.71 (m, 2H), 7.63 (d, J=5.8 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J=9.2Hz, 1H), 6.89 (s, 2H), 5.10 (dd, J=12.3, 5.4 Hz, 1H), 4.41 (s, 2H), 3.98(s, 6H), 3.72 (s, 3H), 3.67-3.55 (m, 6H), 3.17 (d, J=12.9 Hz, 2H),3.05-2.92 (m, 4H), 2.90-2.70 (m, 5H), 2.17-2.00 (m, 3H), 1.81-1.51 (m,5H). LCMS (ESI) m/z: [M+H]⁺=762.45.

Example 49—Preparation of5-[2-(6-[[2,6-Dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D43 Formic Acid)

To a solution of2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde(60.00 mg, 0.190 mmol, 1.00 equiv) and4-(4-[2,6-diazaspiro[3.3]heptan-2-ylmethyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(77.12 mg, 0.190 mmol, 1 equiv) in DMF (1.00 mL) was added NaBH(OAc)₃(80.42 mg, 0.379 mmol, 2 equiv). The resulting solution was stirred atroom temperature for 1 hour. The crude product (60 mg) was purified byPrep-HPLC (conditions: SunFire Prep C18 OBD Column 19×150 mm 5 μm 10 nm;Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 7% B to 10% B in 12 minutes; 254/220 nm; Rt: 9.65minutes) to afford5-[2-(6-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (14.3 mg, 9.82%) as a light yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.54 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.14 (br s, 0.2H,FA), 7.76 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.62-7.54 (m, 1H), 7.19 (d,J=2.2 Hz, 1H), 7.13 (dd, J=8.2, 2.2 Hz, 1H), 6.86 (s, 2H), 5.16 (dd,J=12.8, 5.4 Hz, 1H), 4.47 (s, 2H), 4.34 (s, 4H), 3.98 (s, 6H), 3.95-3.87(m, 2H), 3.80 (s, 4H), 3.71 (s, 3H), 3.00-2.85 (m, 4H), 2.81-2.63 (m,1H), 2.20-2.05 (m, 1H). LCMS (ESI) m/z: [M+H]+=707.5.

Example 50—Preparation of5-((5-(4-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D44 Formic Acid)

Step 1:5-(4-(1,3-dioxolan-2-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(i50-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione(400.0 mg, 1.459 mmol, 1.00 equiv) and 2-(4-bromobutyl)-1,3-dioxolane(305.0 mg, 1.459 mmol, 1.00 equiv) in DMF was added cesium carbonate(475.3 mg, 1.459 mmol, 1.00 equiv) at room temperature. The resultingmixture was filtered, and the filter cake was washed with DCM (3×5 mL).The filtrate was concentrated under reduced pressure. The residue waspurified by Prep-TLC (PE/EtOAc 1:1) to afford5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(40 mg, 6.5%) as an off-white oil. LCMS (ESI) m/z: [M+H]+=403.

Step 2: Preparation of5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal(i50-3)

To a stirred mixture of5-[4-(1,3-dioxolan-2-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(40.0 mg, 0.099 mmol, 1.00 equiv) in water (1.50 mL) was added HCl in1,4-dioxane (4 M, 3.00 mL) at room temperature. The resulting mixturewas stirred for 2 hours at room temperature. The resulting mixture wasextracted with EtOAc (2×10 mL). The combined organic layers were washedwith brine (8 mL), and dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure. The crude productwas used in the next step directly without further purification. LCMS(ESI) m/z: [M+H]+=359.

Step 3: Preparation ofN-(6-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetamideformic acid (Compound D44 Formic Acid)

To a stirred solution/mixture of5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (20mg, 0.056 mmol, 1.00 equiv) in DMF (1 mL) was added4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(22.0 mg, 0.056 mmol, 1 equiv) at room temperature. The resultingmixture was stirred for 30 minutes at room temperature. To the abovemixture was added NaBH(OAc)₃ (23.7 mg, 0.112 mmol, 2.00 equiv) at roomtemperature. The resulting mixture was stirred for additional 2 hours atroom temperature. The crude product was purified by Prep-HPLC(conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 μm 10 nm; MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute;Gradient: 10 B to 25 B in 8 minutes; 254/220 nm; R_(T): 6.53 minutes) toafford5-[[5-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)pentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid (5 mg, 10.9%) as a white solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.54 (d, J=0.9 Hz, 1H), 8.69 (d, J=5.7 Hz, 1H), 8.52 (brs, 0.3H, FA), 7.82 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.62 (dd, J=5.8, 0.9Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.33 (dd, J=8.3, 2.3 Hz, 1H), 6.82 (s,2H), 5.12 (dd, J=12.5, 5.4 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 4.10 (s,2H), 3.93 (s, 6H), 3.72 (s, 3H), 3.12-2.59 (m, 13H), 2.19-2.10 (m, 1H),1.97-1.86 (m, 2H), 1.72-1.54 (m, 4H). LCMS (ESI) m/z: [M+H]+=737.40.

Example 51—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide(Compound D45)

Step 1: Preparation of tert-butyl3-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]sulfamoyl]azetidine-1-carboxylate (i51-2)

To a stirred solution of4-[[2-(2-aminoethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(200.00 mg, 0.555 mmol, 1.00 equiv) and TEA (168.48 mg, 1.665 mmol, 3.00equiv) in DCM (2 mL) was added tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate (170.30 mg, 0.666 mmol, 1.20equiv) at room temperature. The resulting mixture was stirred for 2hours at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by silica gel column chromatography,eluted with CH₂Cl₂/MeOH (7:1) to afford tert-butyl3-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]sulfamoyl]azetidine-1-carboxylate(150 mg, 46.63%) as a yellow solid. LCMS (ESI) m/z: [M−H]+=580.20.

Step 2: Preparation ofN-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide(51-3)

A solution of tert-butyl3-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]sulfamoyl]azetidine-1-carboxylate (100.00 mg, 0.173 mmol, 1.00 equiv)and TFA (1.00 mL) in DCM was stirred for 1 hour at room temperature. Theresulting mixture was concentrated under vacuum. This resulted inN-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide(75 mg, 90.66%) as a red oil. LCMS (ESI) m/z: [M−H]+=480.15.

Step 3: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide(Compound D45)

A solution ofN-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide(30.00 mg, 0.063 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(26.38 mg, 0.081 mmol, 1.30 equiv) in DMF (2.00 mL) was stirred for 20minutes at room temperature. Then NaBH(OAc)₃ (39.78 mg, 0.188 mmol, 3.00equiv) was added to the reaction mixture. The resulting mixture wasstirred for 1 hour at room temperature. The crude product was purifiedby Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; mobile phase, Water (0.1% FA) and ACN (11% PhaseB up to 18%in 20 min, hold 18% in 3 minutes); Detector, UV). This resulted in1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]azetidine-3-sulfonamide(7.9 mg, 16.03%) as a green solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.52(s, 1H), 8.67 (d, J=5.8 Hz, 1H), 8.35 (br s, 0.3H, FA), 7.75 (s, 1H),7.61 (dd, J=5.7, 0.9 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd,J=16.6, 7.8 Hz, 2H), 6.81 (s, 2H), 5.07 (d, J=12.3 Hz, 1H), 4.60 (s,2H), 4.36 (s, 3H), 4.23 (d, J=7.7 Hz, 4H), 3.93 (s, 6H), 3.75 (t, J=5.2Hz, 2H), 3.71 (s, 3H), 3.59 (t, J=5.2 Hz, 2H), 3.53 (t, J=5.2 Hz, 2H),2.92-2.66 (m, 3H), 2.12 (ddd, J=12.7, 6.9, 3.9 Hz, 1H). LCMS (ESI) m/z:[M−H]+=788.26.

Example 52—Preparation of5-(4-(2-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D46 Formic Acid)

Step 1: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)isoindoline-1,3-dione(i52-2)

To a solution of 2-[2-(piperazin-1-yl)ethoxy]ethan-1-ol (315.4 mg, 1.810mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione(500.0 mg, 1.810 mmol, 1.00 equiv) in NMP (5 mL) was added DIEA (467.9mg, 3.620 mmol, 2.00 equiv). The resulting mixture was stirred for 3hours at 90° C. Without any additional work-up, the mixture was purifiedby reverse phase column, elution gradient 0% to 50% ACN in water toafford2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione(700.0 mg, 89.8%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=431.

Step 2: Preparation of2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetaldehyde(i52-3)

A solution of DMSO (54.5 mg, 0.697 mmol, 1.00 equiv) in DCM (6.00 mL)was added slowly to a stirred solution of oxalyl chloride (176.9 mg,1.394 mmol, 2.00 equiv) in DCM (6.00 mL) at −78° C. under nitrogenatmosphere. After 30 minutes2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]isoindole-1,3-dione(300.0 mg, 0.697 mmol, 1.00 equiv) in DCM (6.00 mL) was added slowly.The resulting mixture was stirred for 2 hours at −78° C. and 1.5 hoursat −55° C. Et₃N (0.48 mL, 4.787 mmol, 5.00 equiv) was added slowly at−60° C. After stirring for an additional 10 minutes, the reaction wasallowed to warm to room temperature. The resulting mixture was quenchedwith saturated ammonium chloride aqueous solution (50 mL) and extractedwith DCM (100 mL×3). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered, and concentratedin vacuo. The residue was purified by prep-TLC (EtOAc/PE=1:1) to afford2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetaldehyde(30.0 mg, 5.7%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=429.

Step 3: Preparation of5-(4-(2-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D46 Formic Acid)

To a mixture of2-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)acetaldehyde (30.0 mg, 0.070 mmol, 1.00 equiv) in DMF (2.00 mL) wasadded4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one(23.7 mg, 0.070 mmol, 1.00 equiv). The resulting mixture was stirred for1 hour at room temperature, STAB (29.6 mg, 0.140 mmol, 2.00 equiv) wasadded. The resulting mixture was stirred for 1 hour at room temperature.The resulting mixture, without any additional wok-up, was purified byprep-HPLC (conditions: SunFire C₁₈ OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 5% B to 30% B in 10 minutes; 254 nm;R_(T): 8.82 minutes) to afford5-(4-(2-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)ethoxy)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;formate (6.2 mg, 15.6%) as a light yellow solid. LCMS (ESI) m/z:[M+H]⁺=752.15. ¹H NMR (300 MHz, Methanol-d4) δ 9.47 (s, 1H), 8.64 (d,J=5.8 Hz, 1H), 8.57 (br s, 0.7H), 7.75 (s, 1H), 7.62 (dd, J=12.9, 7.1Hz, 2H), 7.28 (d, J=2.3 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.89 (s, 2H),5.07 (dd, J=12.3, 5.4 Hz, 1H), 4.53 (s, 2H), 3.99 (s, 6H), 3.91 (t,J=4.7 Hz, 2H), 3.76 (t, J=5.1 Hz, 2H), 3.67 (s, 3H), 3.53-3.40 (m, 6H),2.91 (s, 4H), 2.81-2.67 (m, 8H), 2.18-2.05 (m, 1H).

Example 53—Preparation of5-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D47 Formic Acid)

A solution of5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]pentanal (25mg, 0.070 mmol, 1.00 equiv) and4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one(32.4 mg, 0.070 mmol, 1.00 equiv) in DMF (0.8 mL) was stirred for 30minutes at room temperature. NaBH(OAc)₃ (29.57 mg, 0.140 mmol, 2.00equiv) was then added and the resulting mixture was stirred for 1 hourat room temperature. Without any additional work-up, the mixture waspurified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN;Flow rate: 25 mL/minute; Gradient: 7% B to 20% B in 12 minutes; 254 nm;Rt: 11.57 minutes) to afford5-[[5-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pentyl]oxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (7.9 mg, 13%) as a white solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.55 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.50 (br s, 1H,FA), 7.86-7.75 (m, 2H), 7.63 (d, J=5.8 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H),7.32 (dd, J=8.3, 2.3 Hz, 1H), 6.88 (s, 2H), 5.11 (dd, J=12.3, 5.4 Hz,1H), 4.42 (s, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.98 (s, 6H), 3.76 (t, J=4.9Hz, 2H), 3.72 (s, 3H), 3.44-3.35 (3H), 2.93-2.67 (m, 3H), 2.53-2.10 (m,10H), 1.98-1.51 (m, 8H). LCMS (ESI) m/z: [M+H]+=807.50.

Example 54—Preparation ofN-(6-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetamide formic acid (Compound D48 Formic Acid)

Step 1: Preparation of tert-butyl6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate(i54-2)

A solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2.0g, 9.467 mmol, 1.00 equiv) andethyl2-(triphenyl-lambda5-phosphanylidene)acetate (3.63 g, 10.414 mmol,1.10 equiv) in toluene was stirred for 4 hours at 80° C. under nitrogenatmosphere. The resulting mixture was washed with water (3×30 mL). Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (1:1)to afford tert-butyl6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (2.51g, 94.09%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=282.

Step 2: Preparation of tert-butyl6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-3)

To a solution of tert-butyl6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate(2506.00 mg, 8.907 mmol, 1.00 equiv) in MeOH (25 mL) was added Pd/C(10%, 1 g) under nitrogen atmosphere. The mixture was hydrogenated atroom temperature for 1 day under hydrogen atmosphere using a hydrogenballoon, filtered through a Celite pad, and concentrated under reducedpressure afford tert-butyl6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2100.00mg, 81.4%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=284.

Step 3: Preparation of tert-butyl6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-4)

To a stirred solution of tert-butyl6-(2-ethoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g,3.529 mmol, 1.00 equiv) in THF (20 ml) was added LAH (267.88 mg, 7.058mmol, 2 equiv) in portions at 0° C. under nitrogen atmosphere. Thereaction was quenched with Na₂SO₄·10H₂O at room temperature. Theresulting mixture was filtered. The filter cake was washed with MeOH(3×20 mL). The filtrate was concentrated under reduced pressure. Thecrude product (537.00 mg, 63.0%) was used in the next step directlywithout further purification. LCMS (ESI) m/z: [M+H]+=242.

Step 4: Preparation of tert-butyl6-(2-((methylsulfonyl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate(i54-5)

A solution of tert-butyl6-(2-hydroxyethyl)-2-azaspiro[3.3]heptane-2-carboxylate (537.00 mg,2.225 mmol, 1.00 equiv), Et₃N (450.33 mg, 4.450 mmol, 2.00 equiv), andMsCl (280.38 mg, 2.448 mmol, 1.10 equiv) in DCM (5 mL) was stirred for 3hours at room temperature under nitrogen atmosphere. The resultingmixture was extracted with EtOAc (1×20 mL). The combined organic layerswere washed with water (3×10 mL), dried over anhydrous Na₂SO₄, andconcentrated. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (0% to 18%) to afford tert-butyl6-[2-(methanesulfonyloxy)ethyl]-2-azaspiro[3.3]heptane-2-carboxylate(593 mg, 83.43%) as a white solid. LCMS (ESI) m/z: [M+H]+=320

Step 5: Preparation of tert-butyl6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (i54-6)

A solution of tert-butyl6-[2-(methanesulfonyloxy)ethyl]-2-azaspiro[3.3]heptane-2-carboxylate(320.00 mg, 1.002 mmol, 1.00 equiv), Cs₂CO₃ (652.82 mg, 2.004 mmol, 2.00equiv), and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione(274.73 mg, 1.002 mmol, 1.00 equiv) in DMF (3 mL) was stirred for 15hours at room temperature under nitrogen atmosphere. The resultingmixture was extracted with EtOAc (1×100 mL). The combined organic layerswas washed with water (3×100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure toaffordtert-butyl6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)-2-azaspiro[3.3]heptane-2-carboxylate(265.0 Omg, 53.2%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=498.

Step 6: Preparation of5-(2-(2-azaspiro[3.3]heptan-6-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(i54-7)

A solution of tert-butyl6-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (265.00 mg, 0.533 mmol, 1.00 equiv) and TFA (2.5mL) in DCM (5.0 mL) was stirred for 1.5 hours at room temperature undernitrogen atmosphere. The resulting mixture was concentrated underreduced pressure. The residue was purified by Prep-TLC (CH₂Cl₂/EtOAc1:1) to afford5-(2-[2-azaspiro[3.3]heptan-6-yl]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(200 mg, 94.48%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=398.

Step 7: Preparation of5-(2-(2-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D48 Formic Acid)

A solution of5-(2-[2-azaspiro[3.3]heptan-6-yl]ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(51.00 mg, 0.128 mmol, 1.00 equiv) in MeOH (1 mL) was treated with2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(41.62 mg, 0.128 mmol, 1.00 equiv) for 20 minutes at room temperatureunder nitrogen atmosphere followed by the addition of NaBH₃CN (16.13 mg,0.257 mmol, 2.00 equiv) in portions at room temperature. The residue waspurified by reverse flash chromatography (conditions: column, C18 silicagel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes;detector, UV 254 nm). This resulted in5-(2-(2-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formic acid (2.4 mg, 2.2%) as a yellow solid. ¹H NMR(300 MHz, Methanol-d4) δ 9.54 (s, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.56(brs, 1.1H, FA), 7.77 (s, 1H), 7.68-7.56 (m, 2H), 7.13 (d, J=2.2 Hz,1H), 7.05 (dd, J=8.2, 2.2 Hz, 1H), 6.85 (s, 2H), 5.10 (dd, J=12.9, 5.5Hz, 1H), 4.40 (s, 2H), 4.21-4.12 (m, 2H), 4.05 (s, 2H), 3.96 (s, 6H),3.79-3.70 (m, 5H), 2.95-2.84 (m, 2H), 2.75-2.59 (m, 1H), 2.49-2.36 (m,2H), 2.27-2.06 (m, 2H), 2.05-1.92 (m, 2H), 1.72-1.54 (m, 2H). LCMS (ESI)m/z: [M+H]+=706.50.

Example 55—Preparation of5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D49)

Step 1: Preparation of5-(2,2-Diethoxyethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(i55-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (500.00 mg,1.823 mmol, 1.00 equiv) and Cs₂CO₃ (980.20 mg, 3.008 mmol, 3 equiv) inDMF (10.00 mL) was added 2-bromo-1,1-diethoxyethane (538.97 mg, 2.735mmol, 1.5 equiv). The mixture was stirred at 80° C. for 16 hours. Themixture was acidified to pH 6 with HCl (aq.). The mixture was dilutedwith water (40 mL) and extracted with EtOAc/DCM (60 mL×3). The organiclayers were combined and dried over anhydrous sodium sulfate, filtered,and concentrated to give a crude product. The residue was purified byPrep-TLC (PE/EtOAc 1:1) to afford5-(2,2-diethoxyethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(110 mg, 15.45%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=391.

Step 2: Preparation of2-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde(i55-3)

To a stirred solution of5-(2,2-diethoxyethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(100.00 mg, 0.256 mmol, 1.00 equiv) in THF (2.00 mL) was added HCl (4 M)(2.00 mL). The mixture was stirred at room temperature for 4 hours. Themixture was diluted with water (20 mL) and extracted with EtOAc/DCM (30mL×3). The organic layers were combined and dried over anhydrous sodiumsulfate, filtered, and concentrated to give a crude product. Thisresulted in2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde(95 mg, crude) as a white solid. LCMS (ESI) m/z: [M+H]+=317.

Step 3: Preparation of5-[2-(9-[[2,6-Dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(Compound D49)

To a stirred solution of2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetaldehyde(60.00 mg, 0.190 mmol, 1.00 equiv) and4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one(88.13 mg, 0.190 mmol, 1.00 equiv) in DMF (1.50 mL) was added NaBH(OAc)₃(80.42 mg, 0.379 mmol, 2.00 equiv). The mixture was stirred at roomtemperature for 2 hours. Without any additional work-up, the mixture waspurified by prep-HPLC (conditions: Xcelect CSH F-pheny OBD Column,19*250 mm, 5 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN;Flow rate: 25 mL/minute; Gradient: 11 B to 19 B in 12 minutes; 254/220nm; R_(T): 1.70 minutes) to give5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(8.2 mg, 5.52%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.59(s, 1H), 8.71 (s, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.82 (d, J=11.3 Hz, 1H),7.71 (t, J=8.8 Hz, 1H), 7.24-7.05 (m, 2H), 6.85 (d, J=18.8 Hz, 2H),5.32-5.16 (m, 1H), 4.43 (s, 2H), 4.20 (s, 2H), 3.97 (s, 7H), 3.90 (s,1H), 3.75 (s, 3H), 3.59-3.38 (m, 4H), 3.31-3.12 (m, 5H), 3.05-2.86 (m,2H), 2.82-2.63 (m, 1H), 2.47-1.84 (m, 5H). LCMS (ESI) m/z:[M+H]+=765.45.

Example 56—Preparation of5-(4-(9-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D50)

Step 1: Preparation of5-(4,4-dimethoxybutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(i56-2)

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (500.00 mg,1.823 mmol, 1.00 equiv) and 4-chloro-1,1-dimethoxybutane (278.27 mg,1.823 mmol, 1 equiv) in DMF (7.00 mL) was added K₂CO₃ (755.96 mg, 5.470mmol, 3 equiv). The resulting solution was stirred at 80° C. for 12hours. The resulting mixture was extracted with EA (50 mL×2). Thecombined organic layers were washed with saturated NaCl (50 mL) anddried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with EA/PE (100:0) to afford5-(4,4-dimethoxybutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(43.6 mg, 6.13%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=391.

Step 2: Preparation of4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butanal(i56-3)

A solution of5-(4,4-dimethoxybutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(43.60 mg, 0.112 mmol, 1.00 equiv) and HCl (1.00 mL, 4M) in THF (1.00mL) was stirred at 25° C. for 1 hour. The resulting mixture wasextracted with EA (50 mL×2). The combined organic layers were washedwith saturated NaCl (50 mL) and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure toafford4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butanal (34.6mg, 89.98%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=345.

Step 3: Preparation of5-(4-(9-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-y)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D50)

To a solution of4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]butanal(34.00 mg, 0.099 mmol, 1.00 equiv) and4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one(45.87 mg, 0.099 mmol, 1 equiv) in DMF (1.00 mL) was added NaBH(OAc)₃(41.86 mg, 0.197 mmol, 2 equiv). The resulting solution was stirred at25° C. for 1 hour. The mixture was purified by prep-HPLC (conditions:Xselect CSH F-Phenyl OBD Column 19*150 mm 5 μm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 10B to 19 B in 15 minutes; 254/220 nm; R_(T): 14.53 minutes) to afford5-[4-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(14 mg, 17.88%) as an off-white solid. ¹H NMR (300 MHz, Methanol-d4) δ9.57 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.74 (d, J=7.7 Hz,2H), 7.27-7.14 (m, 2H), 6.89 (s, 2H), 5.16 (dd, J=12.8, 5.5 Hz, 1H),4.45 (s, 2H), 4.09-4.01 (m, 2H), 3.98 (s, 6H), 3.89 (t, J=6.4 Hz, 2H),3.73 (s, 3H), 3.57-3.48 (m, 2H), 3.28-3.17 (m, 4H), 2.98-2.87 (m, 2H),2.85-2.59 (m, 2H), 2.41-2.25 (m, 1H), 2.23-2.07 (m, 2H), 2.05-1.90 (m,2H), 1.89-1.59 (m, 5H). LCMS (ESI) m/z: [M+H]+=793.3.

Example 57—Preparation of5-[2-[4-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)piperidin-1-yl]ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid (Compound D51 Formic Acid)

To a solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(30.00 mg, 0.092 mmol, 1.00 equiv) and5-[2-(4-aminopiperidin-1-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(37.04 mg, 0.092 mmol, 1.00 equiv) in MeOH (1 mL) was stirred for 3hours at room temperature under nitrogen atmosphere. To the abovemixture was added NaBH₃CN (11.63 mg, 0.185 mmol, 2.00 equiv), and thereaction was stirred for additional 1 hour at room temperature. To theabove mixture was added HCHO (27.77 mg, 0.925 mmol, 10.00 equiv), andthe reaction was stirred for 1 hour at room temperature under nitrogenatmosphere. Then NaBH₃CN (11.63 mg, 0.185 mmol, 2.00 equiv) was added.The mixture was stirred for overnight at room temperature under nitrogenatmosphere. The crude product (40 mg) was purified by Prep-HPLC(conditions: Gemini-NX C18 AXAI Packed column, 21.2*150 mm 5 μm; MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute;Gradient: 5 B to 17 B in 9 minutes; 254-220 nm; R_(T): 8.30 minutes) toafford5-[2-[4-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)piperidin-1-yl]ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid (7.8 mg) as a white solid. ¹H NMR (300 MHz,DMSO-d6) δ 1.55 (2H, d), 1.77 (2H, d), 2.03 (3H, d), 2.16 (3H, s), 2.44(3H, d), 2.73 (2H, s), 2.88-3.08 (3H, m), 3.61 (5H, s), 3.80 (6H, s),4.30 (2H, s), 5.12 (1H, m), 6.72 (2H, s), 7.38 (1H, m), 7.48 (1H, d),7.57 (1H, d), 7.80-7.90 (2H, m), 8.23 (1H, s), 8.72 (1H, d), 9.45 (1H,s), 11.12 (1H, s). LCMS (ESI) m/z: [M+H]+=723.40.

Example 58—Preparation of5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)propyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D52 Formic Acid)

Step 1: Preparation of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidine-1-carboxylate(i58-2)

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione(1.00 g, 3.647 mmol, 1.00 equiv), tert-butyl4-bromopiperidine-1-carboxylate (0.96 g, 3.634 mmol, 1.00 equiv) andCs₂CO₃ (2.38 g, 7.293 mmol, 2.00 equiv) in DMF (20.00 mL) was stirredfor overnight at 90° C. under air atmosphere. The resulting mixture wasfiltered, and the filter cake was washed with EtOAc (3×10 mL). Thefiltrate was concentrated under reduced pressure. The residue waspurified by Prep-TLC (hexane/EtOAc 1:1) to affordtert-butyl4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidine-1-carboxylate(280 mg, 11.19%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=458.19.

Step 2: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione(i58-3)

A solution of TFA (1.00 mL) and tert-butyl4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidine-1-carboxylate(200.00 mg, 0.437 mmol, 1.00 equiv) in DCM (4.00 mL) was stirred for 2hours at room temperature under air atmosphere. The resulting mixturewas concentrated under reduced pressure to afford2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy) isoindole-1,3-dione(120 mg, 76.81%) as a brown solid. LCMS (ESI) m/z: [M+H]+=358.14.

Step 3: Preparation oftert-butyl(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidin-1-yl)propyl)(methyl)carbamate (i58-4)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindole-1,3-dione(120.00 mg, 0.336 mmol, 1.00 equiv) and tert-butylN-methyl-N-(3-oxopropyl)carbamate (62.87 mg, 0.336 mmol, 1.00 equiv) inMeOH (1.50 mL) was added NaBH₃CN (42.20 mg, 0.672 mmol, 2.00 equiv) inportions at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 2 hours at room temperature under nitrogenatmosphere. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 10:1) toafford tert-butylN-[3-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidin-1-yl)propyl]-N-methylcarbamate(88.00 mg, 49.57%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=529.26.

Step 4: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(methylamino)propyl)piperidin-4-yl)oxy)isoindoline-1,3-dione(i58-5)

A solution of tert-butylN-[3-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]piperidin-1-yl)propyl]-N-methylcarbamate (88.00 mg, 0.166 mmol, 1.00 equiv) and TFA (1.00 mL) in DCM(4.00 mL) was stirred for 1 hour at room temperature. The resultingmixture was concentrated under reduced pressure to afford2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(methylamino)propyl)piperidin-4-yl)oxy)isoindoline-1,3-dione (70 mg, 98.50%) as ayellow solid. LCMS (ESI) m/z: [M+H]+=429.21.

Step 5: Preparation of5-((1-(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)propyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneformic acid (Compound D52 Formic Acid)

A solution of2-(2,6-dioxopiperidin-3-yl)-5-([1-[3-(methylamino)propyl]piperidin-4-yl]oxy)isoindole-1,3-dione(70.00 mg, 0.163 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(52.99 mg, 0.163 mmol, 1.00 equiv) in DMF (3.00 mL) was stirred for 30minutes at room temperature. To the above mixture was added NaBH(AcO)₃(69.25 mg, 0.327 mmol, 2.00 equiv) in portions at room temperature. Theresulting mixture was stirred for additional 2 days at 50° C. Themixture was allowed to cool down to room temperature. The residue waspurified by reverse flash chromatography (conditions: column, C18 silicagel; mobile phase, MeOH in water, 10% to 50% gradient in 10 minutes;detector, UV 254 nm). The crude product (75 mg) was purified byPrep-HPLC (conditions: SunFire C18 OBD Prep Column, 19 mm×250 mm; mobilephase, Water (0.1% FA) and ACN (hold 7% Phase B in 0 min, up to 12% in10 minutes); Detector, UV 254/220 nm) to afford5-([1-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)propyl]piperidin-4-yl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(7.8 mg, 6.48%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.52(s, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.42 (brs, 1.4H, FA), 7.83-7.74 (m,2H), 7.63 (d, J=5.6 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.36-7.28 (m, 1H),6.91 (s, 2H), 5.12 (dd, J=12.5, 5.4 Hz, 1H), 4.76 (s, 1H), 4.45 (s, 2H),4.01 (s, 6H), 3.70 (s, 3H), 3.37 (s, 2H), 3.00 (s, 2H), 2.95-2.84 (m,4H), 2.82-2.63 (m, 6H), 2.22-2.07 (m, 5H), 1.88 (s, 2H). LCMS (ESI) m/z:[M+H]+=737.40.

Example 59—Preparation of5-[3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound D53)

Step 1: Preparation of tert-butyl4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate(i59-2)

To a stirred solution of 2, 6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) benzaldehyde (200.00 mg, 0.617 mmol, 1.00 equiv)and tert-butyl piperazine-1-carboxylate (173.00 mg, 0.929 mmol, 1.51equiv) in MeOH was added NaBH(OAc)₃ (527.00 mg, 2.487 mmol, 4.03 equiv)in portions at room temperature. The resulting mixture was stirred for 3hours at room temperature. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford tert-butyl4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate(204 mg, 66.89%) as a light yellow oil. LCMS (ESI) m/z: [M+H]+=495.

Step 2: Preparation of 4-(3, 5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i59-3)

To a stirred solution of tert-butyl 4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2, 7-naphthyridin-4-yl) phenyl] methyl]piperazine-1-carboxylate (204.00 mg, 0.412 mmol, 1.00 equiv) in DCM wasadded TFA (1.00 mL) dropwise at room temperature. The resulting mixturewas stirred for 1 hour at room temperature. The resulting mixture wasconcentrated under vacuum. The 4-(3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (210 mg crude) was used inthe next step directly without further purification. LCMS (ESI) m/z:[M+H]+=395.

Step 3: Preparation of 4-(4-((4-(3-hydroxypropyl) piperazin-1-yl)methyl)-3, 5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i59-4)

To a stirred solution of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(200.00 mg, 0.507 mmol, 1.00 equiv) and 3-bromopropanol (140.94 mg,1.014 mmol, 2.00 equiv) in acetone was added Cs₂CO₃ (330.38 mg, 1.014mmol, 2.00 equiv) in portions at room temperature. The resulting mixturewas stirred for overnight at room temperature. Desired product could bedetected by LCMS. The resulting mixture was used in the next stepdirectly without further purification. LCMS (ESI) m/z: [M+H]+=453.

Step 4: Preparation of3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propyl methanesulfonate (i59-5)

To a stirred solution of 4-(4-[[4-(3-hydroxypropyl) piperazin-1-yl]methyl]-3, 5-dimethoxyphenyl)-2-methyl-2, 7-naphthyridin-1-one (200.00mg, 0.442 mmol, 1.00 equiv) and Cs₂CO₃ (287.98 mg, 0.884 mmol, 2.00equiv) in acetone was added MsCl (101.25 mg, 0.884 mmol, 2.00 equiv) inportions at room temperature. The resulting mixture was stirred forovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propylmethanesulfonate (92 mg, 39.23%) as a light yellow oil. LCMS (ESI) m/z:[M+H]+=531.

Step 5: Preparation of5-[3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound D53)

To a stirred solution of3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propylmethanesulfonate (90.00 mg, 0.170 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (47.00 mg,0.171 mmol, 1.01 equiv) in DMF was added Na₂CO₃ (36.00 mg, 0.340 mmol,2.00 equiv) in portions at room temperature. The resulting mixture wasstirred for 2 hours at 80° C. The crude product was purified byPrep-HPLC (conditions: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm;mobile phase, Water (0.05% TFA) and ACN (hold 5% Phase B in 2 min, up to22% in 13 minutes); Detector, UV). This resulted in5-[3-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl)propoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(28.1 mg, 23.38%) as an off-white solid. ¹H NMR (300 MHz, Methanol-d4) δ9.59 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.84 (t, J=7.6 Hz,2H), 7.45 (d, J=2.1 Hz, 1H), 7.35 (dd, J=8.3, 2.2 Hz, 1H), 6.89 (s, 2H),5.12 (dd, J=12.4, 5.4 Hz, 1H), 4.49 (s, 2H), 4.30 (t, J=5.7 Hz, 2H),3.97 (s, 6H), 3.75 (s, 3H), 3.57 (s, 4H), 3.16 (s, 2H), 3.45-3.34 (m,4H), 2.99-2.65 (m, 3H), 2.25 (s, 2H), 2.19-2.09 (m, 1H).

LCMS (ESI) m/z: [M+H]+=709.35.

Example 60—Preparation of2-(2,6-dioxopiperidin-3-yl)-4-[4-(9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]isoindole-1,3-dioneformic acid (Compound D54 Formic Acid)

Step 1: Preparation of 7-hydroxy-2-methylisoquinolin-1-one (i60-2)

To a mixture of 7-bromo-2-methylisoquinolin-1-one (500 mg, 2.100 mmol,1.00 equiv), Pd₂(dba)₃ (96.2 mg, 0.105 mmol, 0.05 equiv),tert-BuBrettPhos (101.8 mg, 0.210 mmol, 0.10 equiv), and KOH (353.5 mg,6.300 mmol, 3.00 equiv) was added dioxane (15 mL) and water (5 mL) atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred overnight at 85° C. The mixture was acidified pH 4 with 1 M HCl(aq.) and extracted with EtOAc (3×30 mL). The combined organic layerswere washed with brine (50 mL) and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (1:1 to 3:1) to afford 7-hydroxy-2-methylisoquinolin-1-one (312mg, 85%) as a grey solid. LCMS (ESI) m/z: [M+H]+=176.

Step 2: Preparation of 2-methyl-1-oxoisoquinolin-7-yl acetate (i60-3)

To a stirred solution/mixture of 7-hydroxy-2-methylisoquinolin-1-one(272 mg, 1.553 mmol, 1.00 equiv) and pyridine (614 mg, 7.763 mmol, 5.00equiv) in DCM (6 mL) was added DMAP (10 mg, 0.082 mmol, 0.05 equiv) andAc₂O (46.6 mg, 0.457 mmol, 2.00 equiv) at room temperature. Theresulting mixture was stirred for 1 hour at room temperature. Theresulting mixture was diluted with water (10 mL) and extracted with DCM(2×20 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure to afford 2-methyl-1-oxoisoquinolin-7-yl acetate(335 mg, 99%) as a light brown solid. LCMS (ESI) m/z: [M+H]+=218.

Step 3: Preparation of 4-bromo-2-methyl-1-oxoisoquinolin-7-yl acetate(i60-4)

To a stirred solution/mixture of 2-methyl-1-oxoisoquinolin-7-yl acetate(325 mg, 1.496 mmol, 1.00 equiv) in ACN (10 mL) was added NBS (292.9 mg,1.646 mmol, 1.10 equiv) at room temperature. The resulting mixture wasstirred for 0.5 h at room temperature. The resulting mixture was dilutedwith DCM (30 mL) and washed with 10 mL of water and 10 mL of brine. Theorganic layer was dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue wassuspended in EtOAc (3 mL), then filtered and the light grey solid wascollected as 4-bromo-2-methyl-1-oxoisoquinolin-7-yl acetate (297 mg,67%). LCMS (ESI) m/z: [M+H]+=296.

Step 4: Preparation of4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde(i60-5)

To a mixture of 4-bromo-2-methyl-1-oxoisoquinolin-7-yl acetate (217 mg,0.733 mmol, 1.00 equiv),2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(321.1 mg, 1.099 mmol, 1.50 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (59.8 mg, 0.073mmol, 0.10 equiv), and Cs₂CO₃ (716.3 mg, 2.198 mmol, 3.00 equiv) wasadded dioxane (4 mL) and water (1 mL) at room temperature under N₂atmosphere. The resulting mixture was stirred overnight at 80° C. Theresulting mixture was diluted with sat. NH₄Cl solution (10 mL) andextracted with DCM/i-PrOH (3/1) (5×20 mL). The combined organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with DCM/MeOH (100:1 to 20:1) toafford4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde(248 mg, quant.) as a light brown solid. LCMS (ESI) m/z: [M+H]+=340.

Step 5: Preparation of tert-butyl9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-y)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(i60-6)

A solution of4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde(100mg, 0.295 mmol, 1.00 equiv) and tert-butyl1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (83.1 mg, 0.324 mmol,1.1 equiv) in MeOH (1.5 mL) was stirred for 30 minutes at roomtemperature. Then NaBH₃CN (125 mg, 1.989 mmol, 6.75 equiv) was added.The resulting mixture was stirred for 2 hours at room temperature. Thereaction solution was purified by Prep-TLC (DCM/MeOH 20:1) to affordtert-butyl9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(134 mg, 78%) as a light brown foam. LCMS (ESI) m/z: [M+H]⁺=580.

Step 6: Preparation of4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-7-hydroxy-2-methylisoquinolin-1-one(i60-7)

To a stirred solution/mixture of tert-butyl9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(134 mg,0.231 mmol, 1.00 equiv) in DCM (3 mL) was added TFA (1 mL) at roomtemperature. The resulting mixture was stirred for 30 minutes at roomtemperature. The mixture was concentrated to dryness to give4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-7-hydroxy-2-methylisoquinolin-1-one(135 mg, TFA salt, quant.) as a light brown solid. LCMS (ESI) m/z:[M+H]+=480.

Step 7: Preparation of2-(2,6-dioxopiperidin-3-yl)-4-[4-(9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]isoindole-1,3-dioneformic acid (Compound D54 Formic Acid)

To a stirred solution of4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoic acid(33.8 mg, 0.094 mmol, 0.90 equiv) in DMF (1 mL) was added EDCI (40.0 mg,0.209 mmol, 2.00 equiv) and HOBt (28.2 mg, 0.209 mmol, 2.00 equiv) atroom temperature. The resulting mixture was stirred at room temperaturefor 20 minutes followed by addition of4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-7-hydroxy-2-methylisoquinolin-1-one(50.0 mg, 0.104 mmol, 1.00 equiv) and DIEA (67.4 mg, 0.521 mmol, 5.00equiv). After stirring for 3 hours at room temperature, the reactionmixture was purified by Prep-HPLC (conditions: SunFire Prep C18 OBDColumn, 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), MobilePhase B: ACN; Flow rate: 25 mL/minute; Gradient: 15 B to 24 B in 12minutes; 254/220 nm; R_(T): 11.28 minutes) to afford2-(2,6-dioxopiperidin-3-yl)-4-[4-(9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-oxobutoxy]isoindole-1,3-dione formic acid (11.5 mg, 13%)as an off-white solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 0.5H,FA), 7.84-7.75 (m, 2H), 7.56 (dd, J=8.8, 3.3 Hz, 1H), 7.47 (dd, J=7.6,2.7 Hz, 2H), 7.31-7.19 (m, 2H), 6.82 (d, J=8.8 Hz, 2H), 5.12 (dd,J=12.5, 5.6 Hz, 1H), 4.40-4.20 (m, 4H), 3.93 (d, J=12.4 Hz, 6H),3.78-3.62 (m, 7H), 3.58-3.48 (m, 2H), 3.30-3.17 (m, 4H), 2.97-2.53 (m,5H), 2.24-1.99 (m, 5H), 1.95-1.71 (s, 2H). LCMS (ESI) m/z:[M+H]+=822.40.

Example 61—Preparation of3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide(Compound D55)

Step 1: Preparation of methyl3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate(i61-2)

To a stirred solution of4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one(264.00 mg, 0.778 mmol, 1.20 equiv) and methyl3-formylbicyclo[1.1.1]pentane-1-carboxylate (100.00 mg, 0.649 mmol, 1.00equiv) in MeOH was added NaBH(OAc)₃ (549.91 mg, 2.595 mmol, 4.00 equiv)in portions at room temperature. The resulting solution was stirred for4 hours at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (8:1) to affordmethyl3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-methyl]bicyclo[1.1.1]pentane-1-carboxylate (220 mg, 71.02%) as a light yellowoil. LCMS (ESI) m/z: [M+H]+=478.

Step 2: Preparation of3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (i61-3)

To a stirred solution of methyl3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate(200.00 mg, 0.419 mmol, 1.00 equiv) and LiOH·H₂O (35.15 mg, 0.838 mmol,2.00 equiv) in THF (6 mL) was added H₂O (2.00 mL) dropwise at roomtemperature. The resulting mixture was stirred for overnight at roomtemperature. The mixture was acidified to pH <7 with conc. HCl. Theresulting mixture was concentrated under vacuum. The3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-bicyclo[1.1.1]pentane-1-carboxylicacid (215 mg crude) was used in the next step directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=464.

Step 3: Preparation of3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)-amino)methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide(Compound D55)

To a stirred solution of3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylic acid (50.00 mg,0.108 mmol, 1.00 equiv) and4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(65.44 mg, 0.162 mmol, 1.50 equiv) in DMF were added DIEA (55.76 mg,0.431 mmol, 4.00 equiv) and HATU (61.52 mg, 0.162 mmol, 1.50 equiv) inportions at room temperature. The resulting mixture was stirred for 3 hat room temperature. The crude product was purified by Prep-HPLC withthe following conditions (NB-Prep-HPLC-01): Column, XSelect CSH Prep C18OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.05% TFA) and ACN(16% PhaseB up to 17% in 20 min hold 17% in 8 minutes); Detector, uv.This resulted in3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide; formic acid (4.1 mg, 4.24%) as a yellowsolid. ¹H NMR (300 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.70 (d, J=5.7 Hz,1H), 8.55 (s, 1H), 7.78 (s, 1H), 7.65 (d, J=5.9 Hz, 1H), 7.52 (dd,J=8.6, 7.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.99 (d, J=7.1 Hz, 1H), 6.84(s, 2H), 5.07 (dd, J=12.4, 5.4 Hz, 1H), 4.22 (s, 2H), 3.95 (s, 6H), 3.77(t, J=5.2 Hz, 2H), 3.73 (s, 3H), 3.71-3.65 (m, 4H), 3.59 (t, J=5.4 Hz,2H), 3.52 (t, J=5.2 Hz, 2H), 3.44-3.38 (m, 2H), 3.28-3.24 (m, 1H),2.91-2.81 (m, 1H), 2.80-2.77 (m, 1H), 2.75-2.69 (m, 1H), 2.66 (s, 3H),2.20 (s, 6H), 2.17-2.05 (m, 2H). LCMS (ESI) m/z: [M+H]+=850.45.

Example 62—Preparation of3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamide(Compound D56)

Step 1: Preparation of methyl3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate(i62-2)

To a stirred solution of4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one(264.18 mg, 0.778 mmol, 1.20 equiv) and methyl3-formylbicyclo[1.1.1]pentane-1-carboxylate (100.00 mg, 0.649 mmol, 1.00equiv) in MeOH was added NaBH(OAc)₃ (549.91 mg, 2.595 mmol, 4.00 equiv)in portions at room temperature. The resulting solution was stirred for4 hours at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (8:1) to affordmethyl3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-methyl]bicyclo[1.1.1]pentane-1-carboxylate (220 mg, 71.02%) as a light yellowoil. LCMS (ESI) m/z: [M+H]+=478.

Step 2: Preparation of3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (i62-3)

To a stirred solution of methyl3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylate(200.00 mg, 0.419 mmol, 1.00 equiv) and LiOH·H₂O (35.15 mg, 0.838 mmol,2.00 equiv) in THF (6 mL) was added H₂O (2.00 mL) dropwise at roomtemperature. The resulting mixture was stirred for overnight at roomtemperature. The mixture was acidified to pH <7 with conc. HCl. Theresulting mixture was concentrated under vacuum. The3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (215 mg crude) was used in the next stepdirectly without further purification. LCMS (ESI) m/z: [M+H]+=464.

Step 3: Preparation of3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamide (Compound D56)

To a stirred solution of3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentane-1-carboxylic acid (50.00 mg,0.108 mmol, 1.00 equiv) and4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(65.44 mg, 0.162 mmol, 1.50 equiv) in DMF was added DIEA (55.76 mg,0.431 mmol, 4.00 equiv) and HATU (61.52 mg, 0.162 mmol, 1.50 equiv) inportions at room temperature. The resulting mixture was stirred for 3hours at room temperature. The crude product was purified by Prep-HPLC(conditions: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobilephase, Water (0.05% TFA) and ACN (16% Phase B up to 17% in 20 min hold17% in 8 minutes); Detector, UV). This resulted in3-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)-methyl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)bicyclo[1.1.1]pentane-1-carboxamide(12.3 mg, 13.42%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=804.45.

Example 63—Preparation of3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamide;formic acid (Compound D57 Formic Acid)

Step 1: Preparation ofmethyl-3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)bicyclo[1.1.1]pentane-1-carboxylate(i63-2)

To a solution of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylatehydrochloride (195.2 mg, 1.099 mmol, 1.10 equiv) in MeOH (5.00 mL) wasadded Et₃N (111.0 mg, 1.099 mmol, 1.10 equiv), and then2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(324.0 mg, 0.999 mmol, 1.00 equiv) was added. After 10 minutes stirring,NaBH₃CN (125.6 mg, 1.998 mmol, 2.00 equiv) was added in portions atambient atmosphere. The resulting mixture was concentrated afterstirring for 1 hour at room temperature. The mixture was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]⁺=450.

Step 2: Preparation ofmethyl-3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate(i63-3)

To a solution of crudemethyl-3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)bicyclo[1.1.1]pentane-1-carboxylate obtained last step in MeOH(5.00 mL, 12.349 mmol) was added formaldehyde in water (226.0 μL). After10 min stirring, NaBH₃CN (125.8 mg, 2.002 mmol, 2.00 equiv) was added inportions at ambient atmosphere. The resulting mixture was concentratedafter stirring for 1 hour at room temperature. The mixture was purifiedby Prep-TLC (EtOAc) to affordmethyl-3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate(120 mg, 24.8%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=464.

Step 3: Preparation of3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (i63-4)

A mixture of methyl3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylate(120.0 mg, 0.259 mmol, 1.00 equiv) in conc. HCl (2.00 mL) was stirredfor 1 hour at 90° C. The resulting mixture was concentrated undervacuum. The crude product was used in the next step directly withoutfurther purification. LCMS (ESI) m/z: [M+H]⁺=450.

Step 4: Preparation of3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamideformic acid (Compound D57 Formic Acid)

To a stirred mixture of3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylicacid hydrochloride (50 mg, 0.103 mmol, 1.00 equiv) and4-[(5-aminopentyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;trifluoroacetic acid (53.5 mg, 0.113 mmol, 1.10 equiv) in DMF (2.00 mL)was added DIEA (39.9 mg, 0.309 mmol, 3.00 equiv). The mixture wasstirred at room temperature for 5 minutes, and then HATU (78.2 mg, 0.206mmol, 2.00 equiv) was added. After stirring at room temperature for 2hours, the mixture was purified by Prep-HPLC (conditions: X-select CSHF-Phenyl OBD Column 19*150 mm 5 μm, mobile phase, Water (0.05% TFA) andACN (10% Phase B up to 26% in 15 minutes)). This resulted in of3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)bicyclo[1.1.1]pentane-1-carboxamideformic acid (15.2 mg, 17.2%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.57 (s, 1H), 8.71 (d, J=5.9 Hz, 1H), 8.18 (brs, 0.4H,FA), 7.86 (s, 1H), 7.72 (s, 1H), 7.58 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd,J=7.8, 5.2 Hz, 2H), 6.90 (s, 2H), 5.06 (dd, J=12.0, 5.4 Hz, 1H), 4.51(s, 2H), 3.99 (s, 6H), 3.73 (s, 3H), 3.41-3.35 (m, 2H), 3.31-3.23 (m,2H), 2.89-2.64 (m, 6H), 2.42 (s, 6H), 2.17-2.08 (m, 1H), 1.78-1.67 (m,2H), 1.66-1.56 (m, 2H), 1.54-1.43 (m, 2H). LCMS (ESI) m/z:[M+H]⁺=790.40.

Example 64—Preparation of3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide (Compound D58)

To a stirred mixture of3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentane-1-carboxylicacid (50.0 mg, 0.111 mmol, 1.00 equiv) in DMF (2.00 mL) was added EDCI(42.7 mg, 0.222 mmol, 2.00 equiv) and4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(49.5 mg, 0.122 mmol, 1.10 equiv). The mixture was stirred at roomtemperature for 30 minutes, and then DIEA (71.9 mg, 0.556 mmol, 5.00equiv) and4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(9.9 mg, 0.024 mmol, 1.10 equiv) were added. After stirring at roomtemperature for 2 hours, without any additional work-up, the mixture waspurified by Prep-HPLC (conditions: column, Phenomenex Gemini C6-Phenyl,21.2*250 mm, 5 μm; mobile phase, Water (0.05% FA) and ACN (11% Phase Bup to 21% in 28 minutes). This resulted in3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]bicyclo[1.1.1]pentane-1-carboxamide(10.5 mg, 10.6%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 9.53(s, 1H), 8.69 (d, J=5.7 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J=5.7 Hz, 1H),7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.07 (dd, J=19.4, 7.8 Hz, 2H), 6.74 (s,2H), 5.07 (dd, J=12.3, 5.4 Hz, 1H), 3.88 (s, 6H), 3.77 (t, J=5.2 Hz,2H), 3.73-3.63 (m, 9H), 3.59 (t, J=5.5 Hz, 2H), 3.53 (t, J=5.2 Hz, 2H),3.41 (t, J=5.5 Hz, 2H), 2.90-2.68 (m, 3H), 2.27 (s, 3H), 2.20-2.06 (m,7H). LCMS (ESI) m/z: [M+H]⁺=836.40.

Example 65—Preparation ofN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamideformic acid (Compound D59 Formic Acid)

Step 1: Preparation of tert-butyl(3-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate(i65-2)

To a stirred solution of tert-butylN-[3-aminobicyclo[1.1.1]pentan-1-yl]carbamate (134.49 mg, 0.678 mmol,1.10 equiv) and tert-butyl N-[3-aminobicyclo[1.1.1]pentan-1-yl]carbamate(134.49 mg, 0.678 mmol, 1.00 equiv) in MeOH (3 mL) was added NaBH₃CN(77.50 mg, 1.233 mmol, 2.00 equiv) in portions at room temperature. Theresulting mixture was stirred for 2 hours at room temperature. The cruderesulting mixture was used in the next step directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=507.

Step 2: Preparation of tert-butylN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]carbamate(i65-3)

To a stirred solution of the product from step 1 was added NaBH₃CN(49.62 mg, 0.790 mmol, 2.00 equiv) and formaldehyde (59.27 mg, 1.974mmol, 5.00 equiv) in portions at room temperature. The resulting mixturewas stirred for 2 hours at room temperature. Desired product could bedetected by LCMS. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with CH₂Cl₂/MeOH (8:1) to afford tert-butylN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]carbamate(146 mg, 71.03%) as a light yellow oil. LCMS (ESI) m/z: [M+H]⁺=521.

Step 3: Preparation of4-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)(methyl)amino)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one (i65-4)

To a stirred solution of tert-butylN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]carbamate (146.00 mg,0.300 mmol, 1.00 equiv) in DCM was added TFA (1.00 mL) at roomtemperature. The resulting mixture was stirred for 2 hours at roomtemperature. The resulting mixture was concentrated under reducedpressure to afford4-(4-(((3-aminobicyclo[1.1.1]pentan-1-yl)(methyl)amino)methyl)-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(210 mg crude), which was used in the next step directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=421.

Step 4: Preparation ofN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamideformic acid (Compound D59 Formic Acid)

To a stirred solution of4-[4-[([3-aminobicyclo[1.1.1]pentan-1-yl](methyl)amino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one(80.00 mg, 0.190 mmol, 1.00 equiv) and EDCI (72.94 mg, 0.380 mmol, 2.00equiv) in DMF (1 mL) was added HOBT (51.41 mg, 0.380 mmol, 2.00 equiv)and DIEA (98.35 mg, 0.761 mmol, 4.00 equiv) in portions at roomtemperature. To the above mixture was 25 added3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoicacid (82.45 mg, 0.190 mmol, 1.00 equiv) at room temperature. Theresulting mixture was stirred for additional overnight at roomtemperature. Desired product could be detected by LCMS. The crudeproduct (78.2 mg) was purified by prep-HPLC (conditions: Xselect CSHF-Phenyl OBD column, 19*250, 5 μm; Mobile Phase A: Water (0.05% FA),Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 15 B to 22 B in17 minutes; 254/220 nm; R_(T): 15.32 minutes) to affordN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamideformic acid (23.7 mg, 14.13%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.53 (s, 1H), 8.70 (d, J=5.8 Hz, 1H), 8.20 (brs, 0.3H,FA), 7.78 (s, 1H), 7.63 (d, J=5.7 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H),7.11 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H), 6.85 (s, 2H), 5.08 (dd,J=12.3, 5.4 Hz, 1H), 4.20 (s, 2H), 3.95 (s, 6H), 3.78-3.63 (m, 11H),3.52 (t, J=5.3 Hz, 2H), 2.99-2.66 (m, 6H), 2.52-2.34 (m, 8H), 2.18-2.08(m, 1H). LCMS (ESI) m/z: [M+H]⁺=836.65.

Example 66—Preparation ofN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicyclo[1.1.1]pentan-1-yl]-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamideformic acid (Compound D60 Formic Acid)

To a stirred solution of4-[4-[([3-aminobicyclo[1.1.1]pentan-1-yl](methyl)amino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one (80.00 mg, 0.190 mmol, 1.00equiv) and EDCI (72.94 mg, 0.380 mmol, 2.00 equiv) in DMF (1 mL) wasadded HOBt (51.41 mg, 0.380 mmol, 2.00 equiv) at room temperature. Tothe above mixture was added DIEA (98.35 mg, 0.761 mmol, 4.00 equiv). Theresulting mixture was stirred for overnight at room temperature. Withoutany additional work-up, the mixture was purified by prep-HPLC(conditions: Xselect CSH F-Phenyl OBD column, 19*250, 5 μm; Mobile PhaseA: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute;Gradient: 5 B to 35 B in 13 minutes; 254/220 nm; R_(T): 12.05 minutes)to affordN-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)bicycle[1.1.1]pentan-1-yl]-6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamideformic acid (14.9 mg, 9.36%) as a white solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.53 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.44 (brs, 0.3H,FA), 7.84-7.74 (m, 2H), 7.64 (d, J=5.8 Hz, 1H), 7.46 (d, J=7.9 Hz, 2H),6.78 (s, 2H), 5.10 (dd, J=12.0, 5.4 Hz, 1H), 4.25 (t, J=6.2 Hz, 2H),3.91 (s, 8H), 3.72 (s, 3H), 2.91-2.67 (m, 3H), 2.39 (s, 3H), 2.29-2.20(m, 8H), 2.18-2.08 (m, 1H), 1.91 (p, J=6.5 Hz, 2H), 1.73 (p, J=7.2 Hz,2H), 1.60 (q, J=8.1 Hz, 2H). LCMS (ESI) m/z: [M+H]⁺=791.40.

Example 67—Preparation of5-(2-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D61)

Step 1: Preparation of4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i67-3)

To a stirred solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(500 mg, 1.54 mmol, 1.00 equiv) in MeOH (15 mL) was added NaBH₃CN (290mg, 4.62 mmol, 3.00 equiv) and 3-(prop-2-yn-1-yloxy)azetidinehydrochloride (269 mg, 1.84 mmol, 1.20 equiv). The resulting mixture wasstirred for 2 hours at room temperature. Solvent was removed and theresidue was purified by Flash column chromatography with EtOAc/PE(0-100%) to afford4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(451 mg, 70%) as a solid. LCMS (ESI) m/z: [M+H]⁺=420.4.

Step 2: Preparation of5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(i67-6)

2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82mmol, 1.0 equiv) was dissolved in DMF (15 mL). Potassium carbonate wasthen added (753 mg, 545 mmol, 3 equiv) followed by potassium iodide (451mg, 2.72 mmol, 1.5 equiv) and 1-azido-2-bromoethane (286 mg, 1.91 mmol,1.05 equiv). The mixture was then heated to 80° C. and stirred for 2hours. The solvent was then removed and Flash column chromatography withEtOAc/PE (0-100%), to afford5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (385mg, 62%) as a solid. LCMS (ESI) m/z: [M+H]⁺=344.4.

Step 3: Preparation of5-(2-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D61)

5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20mg, 0.0595 mmol, 1.0 equiv) and4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(25 mg, 0.0595 mmol, 1.0 equiv) were dissolved in DMSO (1 mL). Hünig;sbase (0.020 mL, 0.119 mmol, 2 equiv) was then added followed by CuI(5.69 mg, 0.0297 mmol, 0.5 equiv). The mixture was stirred for 1 hour atroom temperature. The solution was submitted directly for HPLCpurification to give5-(2-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1l-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)azetidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(14.8 mg, 33%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),9.42 (s, 1H), 8.70 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.80 (d, J=8.3Hz, 1H), 7.52 (d, J=5.8 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.31 (dd,J=8.3, 2.3 Hz, 1H), 6.69 (s, 2H), 5.09 (dd, J=12.8, 5.4 Hz, 1H), 4.79(t, J=4.9 Hz, 2H), 4.60 (t, J=5.0 Hz, 2H), 4.39 (s, 2H), 4.00 (t, J=6.1Hz, 1H), 3.83-3.76 (m, 1H), 3.76 (s, 6H), 3.57 (d, J=4.2 Hz, 5H),2.93-2.84 (m, 1H), 2.83 (s, 3H), 2.68-2.63 (m, 2H), 2.59 (s, 1H), 2.54(s, 1H), 2.08-1.95 (m, 2H). LCMS (ESI) m/z: [M+H]+=761.4.

Example 68—Preparation of5-(4-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D62)

Step 1: Preparation of4-(3,5-dimethoxy-4-((methyl(prop-2-yn-1-yl)amino)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i68-3)

To a stirred solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(500 mg, 1.54 mmol, 1.00 equiv) in MeOH (15 mL) was added NaBH₃CN (290mg, 4.62 mmol, 3.00 equiv) and N-methylprop-2-yn-1-amine (127 mg, 1.84mmol, 1.20 equiv). The resulting mixture was stirred for 2 hours at roomtemperature. Solvent was removed and the residue was purified by Flashcolumn chromatography with EtOAc/PE (0-100%), to afford4-(3,5-dimethoxy-4-((methyl(prop-2-yn-1-yl)amino)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(390 mg, 67%) as a solid. LCMS (ESI) m/z: [M+H]⁺=378.7.

Step 2: Preparation of5-azido-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i68-5)

2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81mmol, 1.0 equiv) was dissolved in DMSO (5 mL). Hünig's base was thenadded (0.944 mL, 5.43 mmol, 3 equiv) followed by sodium azide (176 mg,2.71 mmol, 1.5 equiv) and 1-azido-2-bromoethane (286 mg, 1.91 mmol, 1.05equiv). The mixture was then heated to 50° C. and stirred for 2 hours.The solution was then loaded directly onto silica gel and purified oversilica gel with EtOAc/PE (0-100%) to afford5-azido-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (480 mg, 89%)as a solid. LCMS (ESI) m/z: [M+H]⁺=300.1.

Step 3:5-(4-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D62)

5-(2-azidoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (19.8mg, 0.0662 mmol, 1.0 equiv) and4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(25 mg, 0.0662 mmol, 1.0 equiv) were dissolved in DMSO (1 mL). Hünig'sbase (0.023 mL, 0.132 mmol, 2 equiv) was then added followed by CuI (6.3mg, 0.0279 mmol, 0.5 equiv). The mixture was stirred for 1 hour at roomtemperature. The solution was submitted directly for HPLC purificationto5-(4-(((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(12.3 mg, 28%) as a solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H),9.43 (s, 1H), 9.03 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.52-8.45 (m, 2H),8.13 (d, J=14.2 Hz, 1H), 7.85 (s, 1H), 7.54 (d, J=5.7 Hz, 1H), 6.73 (s,2H), 5.20 (dd, J=12.9, 5.3 Hz, 1H), 3.78 (s, 6H), 3.58 (s, 3H),2.96-2.83 (m, 1H), 2.65-2.58 (m, 1H), 2.58-2.50 (m, 1H), 2.22 (s, 5H),2.13-2.03 (m, 1H). LCMS (ESI) m/z: [M+H]+=675.4.

Example 69—Preparation of5-(4-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D63)

Step 1: Preparation of4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)piperidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(i69-3)

To a stirred solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(500 mg, 1.54 mmol, 1.00 equiv) in MeOH (15 mL) was added NaBH₃CN (290mg, 4.62 mmol, 3.00 equiv) and 3-(prop-2-yn-1-yloxy)piperidinehydrochloride (321 mg, 1.84 mmol, 1.20 equiv). The resulting mixture wasstirred for 2 hours at room temperature. Solvent was removed and theresidue was purified by Flash column chromatography with EtOAc/PE(0-100%) to afford4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)piperidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(323 mg, 47%) as a solid. LCMS (ESI) m/z: [M+H]⁺=448.5.

Step 2: Preparation of5-(4-azidobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(i69-6)

2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82mmol, 1.0 equiv) was dissolved in THF (18 mL). Triphenylphosphine wasthen added (571 mg, 2.18 mmol, 1.2 equiv) followed by 4-azidobutan-1-ol(246 mg, 2.91 mmol, 1.05 equiv). The solution was cooled to 0° C. and1-diisopropyl azodicarboxylate (358 mL, 1.82 mmol, 1.0 equiv) was added.The mixture was then warmed to room temperature and stirred for 2 hours.Water was added and the reaction extracted 3 times with ethyl acetate.The organics were dried over MgSO4, filtered, and evaporated. Theresulting oil was columned over silica gel with EtOAc/PE (0-100%), toafford5-(4-azidobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (391mg, 56%) as a solid. LCMS (ESI) m/z: [M+H]⁺=372.4.

Step 3:5-(4-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound D63)

5-(4-azidobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.5mg, 0.0558 mmol, 1.0 equiv) and4-(3,5-dimethoxy-4-((3-(prop-2-yn-1-yloxy)azetidin-1-yl)methyl)phenyl)-2-methyl-2,7-naphthyridin-1(2H)-one(25 mg, 0.0558 mmol, 1.0 equiv) were dissolved in DMSO (1 mL). Hünig'sbase (0.0192 mL, 0.111 mmol, 2 equiv) was then added followed by CuI(5.31 mg, 0.0279 mmol, 0.5 equiv). The mixture was stirred for 1 hour atroom temperature. The solution was submitted directly for HPLCpurification to give5-(4-(4-(((1-(2,6-dimethoxy-4-(2-methyl-1l-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)piperidin-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(6.2 mg, 12%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),8.09 (s, 1H), 7.87 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.77-7.56 (m, 1H),7.39 (d, J=2.3 Hz, 1H), 7.31 (dd, J=8.3, 2.3 Hz, 1H), 6.73 (s, 2H),6.58-6.39 (m, 1H), 5.09 (dd, J=12.9, 5.4 Hz, 1H), 4.59-4.47 (m, 2H),4.42 (t, J=7.0 Hz, 2H), 4.17 (t, J=6.4 Hz, 2H), 3.80 (s, 6H), 3.70 (s,2H), 3.58 (s, 2H), 3.00 (s, 1H), 2.87 (ddd, J=17.4, 14.1, 5.4 Hz, 1H),2.74 (s, 1H), 2.68-2.63 (m, OH), 2.62-2.50 (m, 2H), 2.33-2.27 (m, 1H),2.05 (s, 3H), 2.03-1.93 (m, 1H), 1.97-1.78 (m, OH), 1.71 (q, J=6.7 Hz,3H), 1.40 (s, 1H). LCMS (ESI) m/z: [M+H]⁺=817.2.

Example 70—Preparation of5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D64 Formic Acid)

To a stirred solution of[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetic acid(21.46 mg, 0.065 mmol, 1.00 equiv) and4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-2,7-naphthyridin-1-one(30.00 mg, 0.065 mmol, 1.00 equiv) in DMF (1 mL) was added HATU (49.11mg, 0.129 mmol, 2.00 equiv) and DIEA (33.38 mg, 0.258 mmol, 4.00 equiv)at room temperature. The mixture was stirred at room temperature for 16hours. Without any additional work-up, the mixture was purified byprep-HPLC (conditions: SunFire Prep C18 OBD Column, 19×150 mm 5 μm 10nm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 8 B to 33 B in 10 minutes; 254/220 nm; R_(T): 8.05minutes) to afford5-[2-(9-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid as a white gum (6.8 mg, 12.77%). ¹H NMR (400 MHz,Methanol-d4) δ 9.54 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (brs, 0.3H,FA), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 7.76 (d, J=2.5 Hz, 1H), 7.67-7.62 (m,1H), 7.45 (t, J=2.8 Hz, 1H), 7.40 (dd, J=8.3, 2.2 Hz, 1H), 6.81 (d,J=4.5 Hz, 2H), 5.16-5.00 (m, 3H), 4.18-3.98 (m, 2H), 3.92 (d, J=1.6 Hz,6H), 3.85-3.75 (m, 2H), 3.72 (s, 3H), 3.67-3.59 (m, 2H), 3.56-3.45 (m,2H), 3.11-2.91 (m, 3H), 2.90-2.64 (m, 4H), 2.18-2.09 (m, 1H), 2.08-1.91(m, 2H), 1.85-1.69 (m, 2H). LCMS (ESI) m/z: [M+H]⁺=779.55.

Example 71—Preparation ofN-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide(Compound D65)

Step 1: Preparation of tert-butyl4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (i71-2)

To a stirred solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(100.00mg, 0.308 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate(86.14 mg, 0.462 mmol, 1.50 equiv) in MeOH (1 mL) was added NaBH(OAc)₃(261.38 mg, 1.233 mmol, 4.00 equiv) at room temperature. The resultingmixture was stirred for 2 hours at room temperature. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The crude product was purified by flash silica chromatography,elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford product tert-butyl4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate (115 mg, 75.4%) as a yellow gum. LCMS(ESI) m/z: [M+H]⁺=495.

Step 2: Preparation of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(i71-3)

A solution of tert-butyl4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate(115.00 mg) and TFA (1.00 mL) in DCM (1.00 mL) was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure to afford4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(305 mg, crude), which was used directly without further purification.LCMS (ESI) m/z: [M+H]⁺=395.

Step 3: Preparation ofN-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide(Compound D65)

To a stirred mixture of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(22.05 mg, 0.056 mmol, 1.20 equiv) and2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylicacid (20.00 mg, 0.047 mmol, 1.00 equiv) in DMF (1 mL) was added HATU(35.42 mg, 0.093 mmol, 2.00 equiv) and DIEA (12.04 mg, 0.093 mmol, 2.00equiv) at room temperature. Without any additional work-up, the mixturewas purified by prep-HPLC (conditions: XBridge Shield RP18 OBD Column,30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN;Flow rate: 25 mL/minute; Gradient: 13 B to 22 B in 12 minutes; 254/220nm; R_(T): 9.45 minutes). Pure fractions were evaporated to dryness toaffordN-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamide(12.4 mg, 33.04%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.52(s, 1H), 8.68 (dd, J=5.8, 1.8 Hz, 1H), 8.43 (brs, 0.5H, FA), 7.81 (ddd,J=8.4, 7.3, 3.5 Hz, 1H), 7.75 (d, J=3.7 Hz, 1H), 7.65-7.61 (m, 1H), 7.54(dd, J=6.9, 1.6 Hz, 1H), 7.45 (dd, J=8.3, 2.5 Hz, 1H), 6.76 (d, J=2.5Hz, 2H), 5.19-5.11 (m, 1H), 4.80-4.68 (m, 2H), 3.93-3.81 (m, 9H),3.78-3.68 (m, 5H), 3.51-3.35 (m, 2H), 3.29-3.16 (m, 1H), 2.93-2.67 (m,7H), 2.21-2.06 (m, 2H), 1.72-1.60 (m, 1H), 1.21-1.12 (m, 1H), 1.09-0.99(m, 1H). LCMS (ESI) m/z: [M+H]⁺=806.70.

Example 72—Preparation ofN-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamideformic acid (Compound D66 Formic Acid)

To a stirred mixture of4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-2-methyl-2,7-naphthyridin-1-one(22.05 mg, 0.056 mmol, 1.20 equiv) and2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamido)methyl]cyclopropane-1-carboxylicacid (20.00 mg, 0.047 mmol, 1.00 equiv) in DMF (1 mL) was added HATU(35.42 mg, 0.093 mmol, 2.00 equiv) and DIEA (12.04 mg, 0.093 mmol, 2.00equiv) at room temperature. Without any additional work-up, the mixturewas purified by prep-HPLC (conditions: XBridge Shield RP18 OBD Column,19*250 mm, 10 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN;Flow rate: 25 mL/minute; Gradient: 13 B to 22 B in 12 minutes; 254/220nm; R_(T): 10.22 minutes). Pure fractions were evaporated to dryness toafford N-[[2-(4-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]piperazine-1-carbonyl)cyclopropyl]methyl]-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]acetamide(7.4 mg, 19.18%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.52(s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.46 (brs, 1.0H, FA), 7.82 (d, J=8.3Hz, 1H), 7.73 (s, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H),7.40 (dd, J=8.3, 2.3 Hz, 1H), 6.78 (s, 2H), 5.11 (dd, J=12.4, 5.4 Hz,1H), 4.68 (s, 2H), 3.95 (s, 2H), 3.89 (s, 6H), 3.81 (s, 2H), 3.70 (s,3H), 3.63 (s, 1H), 3.42-3.34 (m, 2H), 3.29-3.20 (m, 1H), 2.94-2.67 (m,7H), 2.18-2.09 (m, 1H), 2.09-2.00 (m, 1H), 1.62 (q, J=7.5 Hz, 1H), 1.11(q, J=5.5 Hz, 1H), 1.01 (td, J=8.1, 4.5 Hz, 1H). LCMS (ESI) m/z:[M+H]⁺=806.40.

Example 73—Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl)azetidine-3-sulfonamide formic acid (Compound D67 Formic Acid)

Step 1: Preparation oftert-butyl-3-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexyl)sulfamoyl]azetidine-1-carboxylate (i73-2)

To a stirred mixture of5-[(6-aminohexyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(60.00 mg, 0.161 mmol, 1.00 equiv) and tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate(102.99 mg, 0.403 mmol, 2.50equiv) in DCM (2.00 mL) was added TEA (48.91 mg, 0.483 mmol, 3.00equiv). After stirring for 1.5 hours at room temperature, the resultingmixture was concentrated under reduced pressure. The residue waspurified by Prep-TLC (CH₂Cl₂/EA=1:2) to affordtert-butyl-3-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexyl)sulfamoyl]azetidine-1-carboxylate(61.8 mg, 60.29%) as a light yellow solid. LCMS (ESI) m/z: [M+H]⁺=592.

Step 2: Preparation ofN-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)azetidine-3-sulfonamide(i73-3)

To a stirred mixture of tert-butyl3-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexyl)sulfamoyl]azetidine-1-carboxylate(61.8 mg, 0.104 mmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (0.40mL, 5.385 mmol, 51.56 equiv). After stirring for 1 hour at roomtemperature, the resulting mixture was concentrated under reducedpressure. The residue was used in the next step directly without furtherpurification. LCMS (ESI) m/z: [M+H]⁺=492.

Step 3: Preparation of1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl)azetidine-3-sulfonamideformic acid (Compound D67 Formic Acid)

A mixture ofN-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl)azetidine-3-sulfonamide(51.36mg, 0.104 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(33.89 mg, 0.104 mmol, 1.00 equiv) in DMF (2 mL) was stirred at roomtemperature. The reaction mixture was then adjusted to pH 8-9 with TEA.To the above mixture was added NaBH₃CN (19.70 mg, 0.313 mmol, 3.00equiv) in portions, and the resulting mixture was stirred for 2 hours atroom temperature. The resulting mixture was concentrated under reducedpressure, the residue was purified by Prep-HPLC (conditions: X SelectCSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water (0.1% FA)and ACN (15% Phase B up to 30% in 14 minutes); Detector, UV). This gave1-[[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl]-N-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino]hexyl)azetidine-3-sulfonamideformic acid (13 mg, 14.12%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6)δ 9.45 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.14 (s, 0.2H, FA), 7.87 (s,1H), 7.56 (d, J=5.7 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.27 (br s, 1H),6.94 (d, J=2.0 Hz, 1H), 6.82 (dd, J=8.2, 2.0 Hz, 1H), 6.78 (s, 2H), 6.56(d, J=8.2 Hz, 2H), 5.10 (dd, J=13.0, 5.4 Hz, 1H), 4.01 (br s, 2H), 3.84(s, 7H), 3.60 (s, 6H), 3.47-3.35 (m, 2H), 3.05-2.83 (m, 3H), 2.77-2.65(m, 1H), 2.49-2.41 (m, 2H), 2.03-1.96 (m, 1H), 1.39 (t, J=7.0 Hz, 4H),1.24 (s, 4H). LCMS (ESI) m/z: [M+H]⁺=800.25.

Example 74—Preparation ofN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamideformic acid (Compound D68 Formic Acid)

Step 1: Preparation of tert-butylN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)methyl]bicyclo[1.1.1]pentan-1-yl]carbamate(i74-2)

To a stirred mixture of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(200.00 mg, 0.617 mmol, 1.00 equiv) and tert-butylN-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]carbamate (144.00 mg, 0.678mmol, 1.10 equiv) in MeOH (1 mL) was added NaBH₃CN (77.50 mg, 1.233mmol, 2.00 equiv) in portions at room temperature. The resulting mixturewas stirred for 2 hours at room temperature. To the above mixture wasadded formaldehyde (0.50 mL). The resulting mixture was stirred for 1hour at room temperature. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 30% EtOAcin petroleum ether. Pure fractions was concentrated under vacuum toafford tert-butylN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)methyl]bicyclo[1.1.1]pentan-1-yl]carbamate (284.8 mg) as a yellow gum. LCMS (ESI) m/z: [M+H]⁺=535.

Step 2: Preparation of4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(i74-3)

A mixture of tert-butylN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]carbamate(284.80 mg) and TFA (1.00 mL) in DCM (1 mL) was stirred for overnight atroom temperature. The reaction mixture was concentrated under vacuum toafford4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(639.4 mg, crude) as a yellow gum. LCMS (ESI) m/z: [M+H]⁺=435.

Step 3: Preparation ofN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamideformic acid (Compound D68 Formic Acid)

To a stirred solution of4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(20.05 mg, 0.046 mmol, 1 equiv) and3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanoicacid (20.00 mg, 0.046 mmol, 1.00 equiv) in DMF (1 mL) was added EDCI(17.69 mg, 0.092 mmol, 2.00 equiv), HOBT (12.47 mg, 0.092 mmol, 2.00equiv), and DIEA (23.86 mg, 0.185 mmol, 4.00 equiv). The resultingmixture was stirred overnight at room temperature. Without anyadditional work-up, the mixture was purified by prep-HPLC (conditions:Column: Gemini-NX C18 AXAI Packed, 21.2*150 mm 5 μm; Mobile Phase A:Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient:8 B to 25 B in 12 minutes; 254/220 nm; R_(T): 11.04 minutes) to affordN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicycle[1.1.1]pentan-1-yl]-3-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]propanamide(3.4 mg, 8.67%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s,1H), 9.45 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 8.29 (s, 1H), 8.23 (brs,1.0H, FA), 7.87 (s, 1H), 7.58 (t, J=7.6 Hz, 2H), 7.14 (d, J=8.6 Hz, 1H),7.03 (d, J=7.1 Hz, 1H), 6.72 (s, 2H), 6.61 (t, J=5.8 Hz, 1H), 5.06 (dd,J=12.7, 5.4 Hz, 1H), 3.81 (s, 6H), 3.58-3.54 (m, 5H), 3.54-3.49 (m, 6H),3.48-3.42 (m, 4H), 2.96-2.81 (m, 1H), 2.64-2.58 (m, 1H), 2.55 (s, 3H),2.26 (t, J=6.4 Hz, 2H), 2.12 (s, 3H), 2.08-1.98 (m, 1H), 1.92 (s, 6H).LCMS (ESI) m/z: [M+H]⁺=850.50.

Example 75—Preparation ofN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methyl]bicyclo[1.1.1]pentan-1-yl]-5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanamide(Compound D69)

To a stirred solution of4-(4-[[([3-aminobicyclo[1.1.1]pentan-1-yl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-2-methyl-2,7-naphthyridin-1-one(23.22 mg, 0.053 mmol, 1.00 equiv) and5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoicacid (20.00 mg, 0.053 mmol, 1.00 equiv) in DMF (1 mL) was added EDCI(20.48 mg, 0.107 mmol, 2.00 equiv) and HOBT (14.44 mg, 0.107 mmol, 2.00equiv) at room temperature. To the above mixture was added DIEA (27.62mg, 0.214 mmol, 4.00 equiv). The resulting mixture was stirred forovernight at room temperature. Without any additional work-up, themixture was purified by prep-HPLC (conditions: SunFire Prep C18 OBDColumn, 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (0.1% FA), MobilePhase B: ACN; Flow rate: 25 mL/minute; Gradient: 13 B to 22 B in 13minutes; 254/220 nm; R_(T): 12.5 minutes) to affordN-[3-[([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)methy-]bicyclo[1.1.1]pentan-1-yl]-5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanamide(6.9 mg, 17.75%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 11.10 (s,1H), 9.46 (d, J=0.8 Hz, 1H), 8.74 (d, J=5.7 Hz, 1H), 8.36 (s, 1H), 7.88(s, 1H), 7.82 (dd, J=8.5, 7.2 Hz, 1H), 7.60-7.42 (m, 3H), 6.79 (s, 2H),5.08 (dd, J=12.8, 5.4 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.86 (s, 6H),3.61 (s, 3H), 3.40 (s, 2H), 2.98-2.80 (m, 2H), 2.62 (s, 2H), 2.46-2.30(m, 4H), 2.15-2.00 (m, 9H), 1.78-1.64 (m, 4H). LCMS (ESI) m/z:[M+H]⁺=791.40.

Example 76—Preparation of5-(4-[2-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)propoxy]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D70 Formic Acid)

Step 1: Preparation of tert-butylN-[3-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)propyl]-N-methylcarbamate(i76-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione(250.00 mg, 0.730 mmol, 1.00 equiv) and tert-butylN-methyl-N-[3-(2-oxoethoxy)propyl]carbamate (168.90 mg, 0.730 mmol, 1equiv) in MeOH (3.00 mL) was added NaBH₃CN (91.78 mg, 1.460 mmol, 2equiv). The mixture was stirred at room temperature for 2 hours. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by Prep-TLC (Petroleum ether/EtOAc 1:3) to affordtert-butylN-[3-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)propyl]-N-methylcarbamate(400 mg, crude) as a dark grey solid. LCMS (ESI) m/z: [M+H]+=558.

Step 2: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[3-(methylamino)propoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione(i76-3)

To a stirred solution of tert-butylN-[3-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)propyl]-N-methylcarbamate(200.00 mg, 0.359 mmol, 1.00 equiv) in DCM (4.00 mL, 62.920 mmol) wasadded TFA (1.00 mg, 0.009 mmol). The mixture was stirred at roomtemperature for 2 hours. The resulting mixture was concentrated underreduced pressure to afford2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[3-(methylamino)propoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione(280 mg, crude) as a dark grey solid. LCMS (ESI) m/z: [M+H]+=458.

Step 3: Preparation of5-(4-[2-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)propoxy]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D70 Formic Acid)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[3-(methylamino)propoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione(100.00 mg, 0.219 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(70.89 mg, 0.219 mmol, 1 equiv) in DMF (1.50 mL) was added NaBH(OAc)₃(92.65 mg, 0.437 mmol, 2 equiv). The mixture was stirred at roomtemperature for 2 hours. The crude product (100 mg) was purified byPrep-HPLC (conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 5 B to 13 B in 15 minutes; 254 nm; R_(T):12.23 minutes) to afford5-(4-[2-[3-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)propoxy]ethyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione;formic acid (10 mg, 5.38%) as a yellow solid. ¹H NMR (300 MHz,Methanol-d4) δ 9.51 (d, J=18.3 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.53(brs, 4.1H, FA), 7.76 (s, 1H), 7.64 (d, J=7.4 Hz, 2H), 7.25 (s, 1H),7.17 (d, J=8.6 Hz, 1H), 6.90 (s, 2H), 5.11-5.04 (m, 2H), 4.69-4.53 (m,2H), 4.47 (s, 2H), 4.00 (s, 6H), 3.74-3.62 (m, 7H), 3.40 (d, J=5.5 Hz,4H), 2.91 (s, 3H), 2.87-2.73 (m, 3H), 2.69 (s, 6H), 2.23-2.08 (m, 3H).LCMS (ESI) m/z: [M+H]⁺=766.45.

Example 77—Preparation of4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetamido]-N-(3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]bicycle[1.1.1]pentan-1-yl)butanamide (Compound D71)

Step 1: Preparation of tert-butylN-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-methylglycinate (i77-2)

To a stirred solution of2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(250.00 mg, 0.771 mmol, 1.00 equiv) and tert-butyl2-(methylamino)acetate (111.92 mg, 0.771 mmol, 1.00 equiv) in MeOH(10.00 mL) was added NaBH₃CN (96.88 mg, 1.542 mmol, 2.00 equiv) inportions at 50° C. under nitrogen atmosphere. The mixture was allowed tocool down to room temperature. The reaction was quenched with Water atroom temperature. The aqueous layer was extracted with EtOAc (3×30 mL).The resulting solid was dried under vacuum. The residue was purified byreverse flash chromatography (conditions: column, C18 silica gel; mobilephase, MeOH in water, 10% to 50% gradient in 10 minutes; detector, UV254 nm). This resulted in tert-butylN-(2,6-dimethoxy-4-(2-methyl-1l-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-methylglycinate(101 mg, 28.92%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=454.

Step 2: Preparation ofN-(2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)-N-methylglycine(i77-3)

A solution of tert-butyl2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino) acetate (101.00 mg, 0.223 mmol, 1.00 equiv) and TFA (7.21 mL,63.270 mmol, 436.14 equiv) in DCM (29.00 mL) was stirred for 15 hours atroom temperature under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum. The residue (108 mg, crude) was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]+=398.

Step 3: Preparation oftert-butyl4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)acetamido)butanoate(i77-4)

A solution of([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)aceticacid (108 mg (crude), 0.272 mmol, 1.00 equiv), DIEA (105.36 mg, 0.815mmol, 3.00 equiv), and HATU (206.53 mg, 0.543 mmol, 2.00 equiv) in DMF(2.00 mL) was stirred for 30 minutes at room temperature under nitrogenatmosphere. To the above mixture was added tert-butyl 4-aminobutanoate(43.27 mg, 0.272 mmol, 1.00 equiv) at room temperature. The resultingmixture was stirred for additional 12 hours at room temperature. Theresidue was purified by reverse flash chromatography (conditions:column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradientin 10 minutes; detector, UV 254 nm). This resulted in tert-butyl4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)acetamido)butanoate (75 mg, 62.33%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=539.

Step 4: Preparation of4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)acetamido)butanoicacid (i77-5)

A solution of tert-butyl4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetamido]butanoate (75.00 mg, 0.139 mmol, 1.00 equiv) and TFA (1 mL) inDCM (4.00 mL) was stirred for 2 hours at room temperature under nitrogenatmosphere. The resulting mixture was concentrated under vacuum. Theresidue (73 mg, crude) was used in the next step directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=483.

Step 5: Preparation of4-(2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)acetamido)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)bicycle[1.1.1]pentan-1-yl)butanamide(Compound D71)

To a stirred solution of4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino) acetamido]butanoic acid (73.00 mg(crude), 0.151 mmol,1.00 equiv), DIEA (58.66 mg, 0.454 mmol, 3.00 equiv), and EDCI (58.00mg, 0.303 mmol, 2.00 equiv) in DMF (2.00 mL) was added HOBT (40.88 mg,0.303 mmol, 2.00 equiv) in portions at room temperature under nitrogenatmosphere. The reaction mixture was irradiated with microwave radiationfor 1 hour at room temperature. To the above mixture was added4-([3-aminobicyclo[1.1.1]pentan-1-yl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (53.61 mg, 0.151 mmol, 1.00 equiv) at roomtemperature. The resulting mixture was stirred for additional 2 days atroom temperature. The residue was purified by reverse flashchromatography (conditions: column, C18 silica gel; mobile phase, MeOHin water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm). Thecrude product (70 mg) was purified by Prep-HPLC (conditions: AtlantisHILIC OBD Column 19*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 40 mL/minute; Gradient: 24% B to 24% Bin 12 minutes; 254/220 nm; Rt: 11.43 minutes) to afford4-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)acetamido]-N-(3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]bicyclo[1.1.1]pentan-1-yl)butanemide(10 mg, 8.07%) as a light yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ9.56 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.75 (d,J=5.9 Hz, 1H), 7.58 (dd, J=9.5, 5.0 Hz, 1H), 7.27 (dd, J=8.6, 3.5 Hz,1H), 7.14 (d, J=7.2 Hz, 1H), 6.89 (s, 2H), 5.08 (dd, J=12.4, 5.4 Hz,1H), 4.56 (d, J=5.7 Hz, 2H), 4.01-3.97 (m, 7H), 3.93-3.87 (m, 1H), 3.73(s, 3H), 3.29-3.23 (m, 2H), 2.97 (s, 3H), 2.90-2.83 (m, 1H), 2.80-2.68(m, 2H), 2.43 (s, 6H), 2.22 (t, J=7.3 Hz, 2H), 2.16-2.10 (m, 1H), 1.80(p, J=7.2 Hz, 2H). LCMS (ESI) m/z: [M+H]⁺=819.35.

Example 78—Preparation ofN-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methylpentanamide formic acid (Compound D72 Formic Acid)

Step 1: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-y]isoindole-1,3-dione(i78-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430mmol, 1.00 equiv) and tert-butyl1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (1.67 g, 6.516 mmol,1.20 equiv) in NMP (10.00 mL) was added DIEA (1.40 g, 10.861 mmol, 2.00equiv) dropwise at room temperature. The resulting mixture was stirredfor 6 hours at 90° C. under nitrogen atmosphere. The residue waspurified by reverse flash chromatography (conditions: column, C18 silicagel; mobile phase, ACN in water, 10% to 50% gradient in 20 minutes;detector, UV 254 nm). This resulted in tert-butyl9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(2 g, 72%) as a green oil. LCMS (ESI) m/z: [M+H]+=513.

Step 2: Preparation of2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione(i78-3)

To a stirred solution of tert-butyl9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(430.00 mg, 0.839 mmol, 1.00 equiv) in DCM (3.50 mL) was added TFA (1.00mL). The mixture was stirred at room temperature for 1 hour. Theresulting mixture was concentrated under reduced pressure to afford2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione (670 mg, crude) as a yellow solid.LCMS (ESI) m/z: [M+H]+=413

Step 3: Preparation of methyl5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate(i78-4)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione(200.00 mg, 0.485 mmol, 1.00 equiv) and methyl 5-oxopentanoate (75.73mg, 0.582 mmol, 1.2 equiv) in MeOH (2.00 mL) was added NaBH₃CN (60.95mg, 0.970 mmol, 2 equiv). The mixture was stirred at room temperaturefor 2 hours. The resulting mixture was concentrated under reducedpressure. The residue was purified by Prep-TLC (Petroleum ether/EtOAc1:3) to afford methyl5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate(80 mg, 31.33%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=527.

Step 4: Preparation of5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoic acid (i178-5)

Methyl5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate(70.00 mg, 0.133 mmol, 1.00 equiv) was stirred at room temperature withHCl (aq.) for 2 hours. The resulting mixture was concentrated underreduced pressure. This resulted in5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoicacid (70 mg, crude) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=513.

Step 5: Preparation ofN-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methylpentanamideformic acid (Compound D72 Formic Acid)

To a stirred solution of5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoic acid (55.00 mg, 0.107 mmol, 1.00 equiv) and4-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-2-methyl-2,7-naphthyridin-1-one(36.42 mg, 0.107 mmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA(69.34 mg, 0.537 mmol, 5.00 equiv) and HATU (61.20 mg, 0.161 mmol, 1.50equiv). The mixture was stirred at room temperature for 1 hours. Thecrude product (55 mg) was purified by Prep-HPLC (conditions: SunFire C18OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 9 B to 28 Bin 13 minutes; 254 nm; R_(T): 14.08 minutes) to affordN-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methylpentanamideformic acid (8.2 mg, 8.68%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.50 (d, J=3.4 Hz, 1H), 8.65 (dd, J=12.4, 5.8 Hz, 1H),8.39 (brs, 0.6H, FA), 7.74 (d, J=4.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.28(dd, J=12.7, 2.3 Hz, 1H), 7.22-7.14 (m, 1H), 6.80 (d, J=20.6 Hz, 2H),5.04 (dt, J=12.8, 5.8 Hz, 1H), 4.75 (d, J=16.1 Hz, 2H), 3.90 (d, J=16.5Hz, 6H), 3.87-3.82 (m, 2H), 3.74-3.63 (m, 5H), 3.32-3.26 (m, 2H),2.92-2.82 (m, 2H), 2.78 (d, J=6.8 Hz, 4H), 2.73-2.53 (m, 7H), 2.47 (t,J=6.7 Hz, 1H), 2.17-2.01 (m, 3H), 1.82-1.62 (m, 6H). LCMS (ESI) m/z:[M+H]⁺=834.40.

Example 79—Preparation of2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)acetamide formic acid (Compound D73 FormicAcid)

Step 1: Preparation of tert-butylN-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)carbamate(i79-2)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione(200.00 mg, 0.485 mmol, 1.00 equiv) and tert-butylN-(4-oxobutyl)carbamate (907.94 mg, 4.849 mmol, 10.00 equiv) in DMF(1.50 mL) was added NaBH₃CN (60.95 mg, 0.970 mmol, 2.00 equiv). Themixture was stirred at room temperature for 5 hours. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-TLC (Petroleum ether/EtOAc 1:3) to afford tert-butylN-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)carbamate(200 mg, crude) as a yellow solid. LCMS (ESI) m/z: [M+H]+=584.

Step 2: Preparation of5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(i79-3)

To a stirred solution of tert-butylN-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)carbamate(200.00 mg, 0.343 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (1.00mL). The mixture was stirred at room temperature for 2 hours. Theresidue was purified by Prep-TLC (CH₂Cl₂/MeOH 10:1) to afford5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(60 mg, 36.21%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=484.

Step 3: Preparation of2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)acetamideformic acid (Compound D73 Formic Acid)

To a stirred solution of5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(60.00 mg, 0.124 mmol, 1.00 equiv) and([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)aceticacid (49.31 mg, 0.124 mmol, 1.00 equiv) in DMF (1.00 mg) was added DIEA(80.18 mg, 0.620 mmol, 5.00 equiv) and HATU (70.77 mg, 0.186 mmol, 1.50equiv). The mixture was stirred at room temperature for 1 hour. Thecrude product (60 mg) was purified by Prep-HPLC (conditions: SunFire C18OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 8 B to 17 Bin 12 minutes; 254 nm; R_(T): 11.87 minutes) to afford2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)acetamideformic acid (12.6 mg, 10.72%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J=5.8 Hz, 1H), 8.53 (brs, 0.9H,FA), 7.74 (s, 1H), 7.62 (dd, J=7.3, 6.3 Hz, 2H), 7.27 (d, J=2.3 Hz, 1H),7.16 (dd, J=8.6, 2.4 Hz, 1H), 6.82 (s, 2H), 5.05 (dd, J=12.7, 5.5 Hz,1H), 4.15 (s, 2H), 3.94 (s, 6H), 3.75 (t, J=4.8 Hz, 2H), 3.69 (s, 3H),3.64 (d, J=13.0 Hz, 2H), 3.54 (s, 2H), 3.31-3.25 (m, 4H), 2.94-2.81 (m,1H), 2.80-2.68 (m, 2H), 2.63 (s, 3H), 2.46 (s, 2H), 2.37 (t, J=6.6 Hz,2H), 2.32 (s, 2H), 2.17-2.00 (m, 3H), 1.68-1.51 (m, 6H). LCMS (ESI) m/z:[M+H]⁺=863.50.

Example 80—Preparation of5-[(1-[2-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)ethoxy]acetyl]azetidin-3-yl)methoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D74 Formic Acid)

Step 1: Preparation of tert-butylN-(2-[2-[3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]methyl)azetidin-1-yl]-2-oxoethoxy]ethyl)carbamate (i80-2)

To a solution of [2-[(tert-butoxycarbonyl)amino]ethoxy]acetic acid(30.65 mg, 0.140 mmol, 1.20 equiv) and HATU (88.60 mg, 0.233 mmol, 2.00equiv) in DMF (1.00 mL) was added5-(azetidin-3-ylmethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(40.00 mg, 0.117 mmol, 1.00 equiv) and DIEA (45.17 mg, 0.350 mmol, 3.00equiv), and the resulting solution was stirred at 25° C. for 2 hours.The resulting mixture was concentrated. The residue was applied onto asilica gel column with CH₂Cl₂/MeOH (20:1). This resulted in (50 mg,78.81%) of tert-butylN-(2-[2-[3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]methyl)azetidin-1-yl]-2-oxoethoxy]ethyl)carbamateas a yellow solid. LCMS (ESI) m/z: [M+H]+=545.30.

Step 2: Preparation of5-([1-[2-(2-aminoethoxy)acetyl]azetidin-3-yl]methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(i80-3)

To a solution of tert-butylN-(2-[2-[3-([[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]methyl)azetidin-1-yl]-2-oxoethoxy]ethyl)carbamate (50.00 mg, 0.092 mmol, 1.00equiv) in TFA (2.00 mL) and DCM (2.00 mL), and the resulting solutionwas stirred at 25° C. for 2 hours. The resulting mixture wasconcentrated and used directly without further purification. Thisresulted in (60 mg, crude) of5-([1-[2-(2-aminoethoxy)acetyl]azetidin-3-yl]methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneas a yellow solid. LCMS (ESI) m/z: [M+H]+=445.50.

Step 3: Preparation of5-[(1-[2-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)ethoxy]acetyl]azetidin-3-yl)methoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneformic acid (Compound D74 Formic Acid)

To a solution of5-([1-[2-(2-aminoethoxy)acetyl]azetidin-3-yl]methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(20 mg, 0.045 mmol, 1.00 equiv) and2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde(17.51 mg, 0.054 mmol, 1.20 equiv) in DMF (2.00 mL) was added NaBH₃CN(5.66 mg, 0.090 mmol, 2.00 equiv). The resulting solution was stirred at25° C. for 2 hours. The resulting mixture was concentrated. The crudeproduct was purified by preparative HPLC Column: XSelect CSH Prep C18OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), MobilePhase B: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 55% B in 8minutes; 254 nm; R_(t): 7.12 minutes). This resulted in (10 mg, 27.82%)of5-[(1-[2-[2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]amino)ethoxy]acetyl]azetidin-3-yl)methoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dioneas an off-white solid. ¹H NMR (400 MHz, Methanol-d4) δ 9.53 (s, 1H),8.68 (d, J=5.8 Hz, 1H), 8.57 (brs, 3.2H, FA), 7.82 (d, J=8.3 Hz, 1H),7.76 (s, 1H), 7.61 (d, J=5.7 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.35 (dd,J=8.1, 2.3 Hz, 1H), 6.84 (s, 2H), 5.12 (dd, J=12.6, 5.4 Hz, 1H), 4.40(t, J=8.8 Hz, 1H), 4.35 (d, J=3.8 Hz, 4H), 4.27-4.13 (m, 4H), 4.02-3.93(m, 7H), 3.83 (t, J=4.9 Hz, 2H), 3.71 (s, 3H), 3.27-3.21 (m, 3H),2.94-2.83 (m, 1H), 2.82-2.67 (m, 2H), 2.20-2.10 (m, 1H). LCMS (ESI) m/z:[M+H]+=753.40.

Example 81—Preparation of Compounds D75-D177

In analogy to the procedures described in the examples above, compoundsD75-D177 were prepared using the appropriate starting materials.

Compound No. Analytical Data D75 LCMS: (ESI) m/z: [M + H]⁺ = 835.70 D76LCMS: (ESI) m/z: [M + H]⁺ = 788.20 D77 LCMS: (ESI) m/z: [M + H]⁺ =774.10 D78 LCMS: 789.2; ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.45(s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.21 (s, 0.7H, FA), 8.05 (d, J =7.5Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.59-7.54 (m, 1H),7.31-7.24 (m, 2H), 6.73 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.87(t, J = 6.8 Hz, 1H), 4.14-3.99 (m, 1H), 3.81 (s, 6H), 3.66 (s, 2H), 3.61(s, 3H), 3.44-3.35 (m, 3H), 2.98 (s, 2H), 2.92-2.83 (m, 1H), 2.73-2.55(m, 4H), 2.44-2.32 (m, 1H), 2.25 (dd, J = 18.0, 6.8 Hz, 3H), 2.15-2.00(m, 3H), 1.95 (td, J = 11.2, 8.4 Hz, 2H). D79 LCMS: (ESI) m/z: [M + H]⁺= 789.20; ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.45 (s, 1H), 8.73(d, 5.7 Hz, 1H), 8.21 (s, 0.7H, FA), 8.05 (d, J = 7.5 Hz, 1H), 7.87 (s,1H), 7.82 (d, J = 8.2 Hz, 1H), 7.59-7.54 (m, 1H), 7.31-7.24 (m, 2H),6.73 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (t, J = 6.8 Hz, 1H),4.14-3.99 (m, 1H), 3.81 (s, 6H), 3.66 (s, 2H), 3.61 (s, 3H), 3.44-3.35(m, 3H), 2.98 (s, 2H), 2.92-2.83 (m, 1H), 2.73-2.55 (m, 4H), 2.44-2.32(m, 1H), 2.25 (dd, J = 18.0, 6.8 Hz, 3H), 2.15-2.00 (m, 3H), 1.95 (td, J= 11.2, 8.4 Hz, 2H). D80 LCMS: (ESI) m/z: [M + H]⁺ = 803.15; ¹H NMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.6 Hz, 1H),8.21 (s, 0.6H, FA), 7.97- 7.77 (m, 2H), 7.56 (d, J = 5.7 Hz, 1H),7.37-7.20 (m, 2H), 6.74 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H),5.10-4.97 (m, 1H), 3.82 (d, J = 2.0 Hz, 6H), 3.70 (s, 2H), 3.61 (s, 3H),3.36 (s, 5H), 3.09-2.95 (m, 2H), 2.88 (d, J = 13.9 Hz, 1H), 2.58 (d, J =10.3 Hz, 8H), 2.16-1.99 (m, 1H), 1.87 (d, J = 9.8 Hz, 2H), 1.63 (s, 1H),1.55 (s, 2H), 1.47 (s, 1H). D81 LCMS: (ESI) m/z: [M + H]⁺ = 715.20 D82LCMS: (ESI) m/z: [M + H]⁺ = 821.25; ¹H NMR (300 MHz, Methanol-d4) δ 9.54(d, J = 0.9 Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.54 (s, 0.4H, FA),7.86-7.75 (m, 2H), 7.63 (dd, J = 5.8, 0.9 Hz, 1H), 7.50 (dd, J = 7.8,5.7 Hz, 2H), 6.87 (s, 2H), 5.14 (dd, J = 12.3, 5.4 Hz, 1H), 4.44-4.32(m, 4H), 4.24 (p, J = 8.3 Hz, 1H), 3.97 (s, 6H), 3.93-3.83 (m, 4H), 3.72(s, 3H), 3.22-3.02 (m, 2H), 2.99-2.65 (m, 4H), 2.46 (t, J = 5.9 Hz, 2H),2.27 (s, 2H), 2.22-2.09 (m, 2H), 1.91 (s, 2H), 1.76 (s, 4H). D83 LCMS:(ESI) m/z: [M + H]⁺ = 781.55; ¹H NMR (300 MHz, Methanol-d4) δ 9.53 (s,1H), 8.69 (d, J = 6.0 Hz, 1H), 7.85 (s, 1H), 7.82-7.66 (m, 2H), 7.50-7.36 (m, 2H), 6.85 (d, J = 1.2 Hz, 2H), 5.12 (dd, J = 12.5, 5.4 Hz, 1H),4.50 (s, 1H), 4.42 (s, 1H), 4.35-4.11 (m, 4H), 4.02 (dd, J = 11.0, 6.7Hz, 1H), 3.94 (d, J = 2.7 Hz, 6H), 3.91-3.76 (m, 5H), 3.71 (d, J = 1.5Hz, 3H), 3.22 (t, J = 6.5 Hz, 2H), 3.08-2.59 (m, 4H), 2.46 (t, J = 5.8Hz, 2H), 2.21-2.07 (m, 1H), 1.84 (p, J = 7.2, 6.7 Hz, 2H). D84 LCMS:(ESI) m/z: [M + H]⁺ = 793.55 D85 LCMS: (ESI) m/z: [M + H]⁺ = 807.25 D86LCMS: (ESI) m/z: [M + H]⁺ = 779.20 D87 LCMS: (ESI) m/z: [M + H]⁺ =793.45 D88 LCMS: (ESI) m/z: [M + H]⁺ = 807.90; ¹H NMR (400 MHz,Methanol-d4) δ 9.55 (d, J = 0.8 Hz, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.56(s, 0.5H, FA), 7.86-7.73 (m, 2H), 7.63 (d, J = 5.8 Hz, 1H), 7.48 (dd, J= 7.9, 6.2 Hz, 2H), 6.85 (s, 2H), 5.24-5.02 (m, 1H), 4.38 (t, J = 4.3Hz, 2H), 4.33 (s, 2H), 3.95 (s, 6H), 3.93-3.81 (m, 4H), 3.72 (s, 4H),3.71-3.40 (m, 4H), 3.25-3.01 (m, 3H), 2.98-2.82 (m, 2H), 2.82-2.61 (m,3H), 2.21-2.07 (m, 1H), 1.91 (s, 2H), 1.63 (d, J = 17.7 Hz, 4H). D89LCMS: (ESI) m/z: [M + H]⁺ = 821.30 D90 LCMS: (ESI) m/z: [M + H]⁺ =793.45 D91 LCMS: (ESI) m/z: [M + H]⁺ = 807.50 D92 LCMS: (ESI) m/z: [M +H]⁺ = 793.60; ¹H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.68 (dd, J= 5.8, 2.4 Hz, 1H), 8.52 (s, 0.5H, FA), 7.90-7.73 (m, 2H), 7.62 (s, 1H),7.47 (dd, J = 9.3, 3.5 Hz, 2H), 6.89-6.74 (m, 2H), 5.24- 5.04 (m, 1H),4.31 (d, J = 33.1 Hz, 5H), 3.90 (dd, J = 6.6, 4.5 Hz, 12H), 3.78- 3.58(m, 7H), 3.00-2.48 (m, 6H), 2.26-1.78 (m, 3H). D93 LCMS: (ESI) m/z: [M +H]⁺ = 793.50 D94 LCMS: (ESI) m/z: [M + H]⁺ = 865.55 D95 LCMS: (ESI) m/z:[M + H]⁺ = 793.65 D96 LCMS: (ESI) m/z: [M + H]⁺ = 835.45 D97 LCMS: (ESI)m/z: [M + H]⁺ = 865.50; ¹H NMR (300 MHz, Methanol-d4) δ 9.54 (d, J = 0.8Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.55 (s, 0.6H, FA), 7.90-7.71 (m,2H), 7.64 (d, J = 5.8 Hz, 1H), 7.48 (dd, J = 7.9, 3.5 Hz, 2H), 6.87 (s,2H), 5.12 (dd, J = 12.3, 5.4 Hz, 1H), 4.50-4.23 (m, 4H), 3.97 (s, 6H),3.95- 3.79 (m, 5H), 3.72 (s, 5H), 3.66 (dd, J = 5.8, 1.9 Hz, 1H),3.59-3.32 (m, 3H), 3.30-2.98 (m, 2H), 2.98-2.59 (m, 6H), 2.25-1.70 (m,7H), 1.49 (s, 2H). D98 LCMS: (ESI) m/z: [M + H]⁺ = 779.40; ¹H NMR (400MHz, Methanol-d4) δ 9.51 (d, J = 1.5 Hz, 1H), 8.67 (d, J = 5.7 Hz, 1H),7.69 (d, J = 1.8 Hz, 1H), 7.63- 7.49 (m, 2H), 7.27 (dd, J = 5.8, 2.3 Hz,1H), 7.16 (ddd, J = 11.0, 8.4, 2.3 Hz, 1H), 6.65 (d, J = 2.1 Hz, 2H),5.04 (td, J = 12.4, 5.5 Hz, 1H), 4.80 (d, J = 10.2 Hz, 1H), 4.33 (d, J =10.5 Hz, 2H), 4.25 (d, J = 16.3 Hz, 2H), 4.03 (d, J = 11.4 Hz, 1H),3.95-3.74 (m, 12H), 3.74 (d, J = 1.3 Hz, 4H), 3.39-3.30 (m, 1H), 2.80(dt, J = 13.9, 4.7 Hz, 1H), 2.76-2.54 (m, 3H), 2.46-2.22 (m, 3H), 2.03(td, J = 7.3, 6.8, 3.3 Hz, 1H). D99 LCMS: (ESI) m/z: [M + H]⁺ = 793.45D100 LCMS: (ESI) m/z: [M + H]⁺ = 793.35 D101 LCMS: (ESI) m/z: [M + H]⁺ =793.45; ¹H NMR (300 MHz, Methanol-d4) δ 9.53 (d, J = 0.8 Hz, 1H), 8.69(d, J = 5.8 Hz, 1H), 8.56 (s, 0.7H, FA), 7.86-7.73 (m, 2H), 7.64-7.56(m, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.3, 2.3 Hz, 1H), 6.84(s, 2H), 5.12 (dd, J = 12.4, 5.4 Hz, 1H), 4.36-4.20 (m, 4H), 4.20-4.05(m, 3H), 3.96 (d, J = 8.5 Hz, 8H), 3.90-3.75 (m, 4H), 3.71 (s, 3H),2.97-2.55 (m, 5H), 2.43 (t, J = 5.9 Hz, 2H), 2.25-2.08 (m, 3H). D102LCMS: (ESI) m/z: [M + H]⁺ = 761.2 D103 LCMS: (ESI) m/z: [M + H]⁺ = 747.3D104 LCMS: (ESI) m/z: [M + H]⁺ = 747.3 D105 LCMS: (ESI) m/z: [M + H]⁺ =719.3 D106 LCMS: (ESI) m/z: [M + H]⁺ = 733.4 D107 LCMS: (ESI) m/z: [M +H]⁺ = 733.3 D108 LCMS: (ESI) m/z: [M + H]⁺ = 807.45 D109 LCMS: (ESI)m/z: [M + H]⁺ = 865.35 D110 LCMS: (ESI) m/z: [M + H]⁺ = 835.75 D111LCMS: (ESI) m/z: [M + H]⁺ = 793.50 D112 LCMS: (ESI) m/z: [M + H]⁺ =793.50 D113 LCMS: (ESI) m/z: [M + H]⁺ = 779.35 D114 LCMS: (ESI) m/z:[M + H]⁺ = 851.25 D115 LCMS: (ESI) m/z: [M + H]⁺ = 793.45 D116 LCMS:(ESI) m/z: [M + H]⁺ = 821.30 D117 LCMS: (ESI) m/z: [M + H]⁺ = 781.60; ¹HNMR (300 MHz, Methanol-d4) δ 9.51 (s, 1H), 8.68 (d, J = 5.8 Hz, 1H),8.56 (s, 0.7H, FA), 7.76 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 5.8 Hz, H),7.39 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (s, 2H),5.10 (dd, J = 12.5, 5.4 Hz, 1H), 4.37 (s, 2H), 4.33-4.24 (m, 2H),4.22-4.08 (m, 2H), 3.95 (s, 6H), 3.85 (dq, J = 7.2, 5.7 Hz, 6H), 3.70(s, 3H), 3.20 (t, J = 6.5 Hz, 2H), 3.02-2.62 (m, 4H), 2.47 (t, J = 5.8Hz, 2H), 2.23-2.05 (m, 1H), 1.84 (q, J = 6.9 Hz, 2H). D118 LCMS: (ESI)m/z: [M + H]⁺ = 807.60; ¹H NMR (300 MHz, Methanol-d4) δ 9.53 (d, J = 0.8Hz, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.55 (s, 0.7H, FA), 7.89-7.75 (m,2H), 7.61 (dd, J = 5.8, 0.8 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.37-7.30(m, 1H), 6.85 (s, 2H), 5.10 (dd, J = 12.4, 5.4 Hz, 1H), 4.41 (s, 2H),4.35- 4.25 (m, 2H), 3.95 (s, 6H), 3.91-3.77 (m, 8H), 3.72 (s, 3H), 3.54(q, J = 5.6 Hz, 4H), 2.96-2.63 (m, 5H), 2.12 (dtd, J = 12.8, 4.8, 2.1Hz, 1H), 1.83 (dt, J = 16.1, 5.8 Hz, 4H). D119 LCMS: (ESI) m/z: [M + H]⁺= 807.45 D120 LCMS: (ESI) m/z: [M + H]⁺ = 821.45 D121 LCMS: (ESI) m/z:[M + H]⁺ = 807.40; ¹H NMR (400 MHz, Methanol-d4) δ 9.53 (d, J = 1.0 Hz,1H), 8.69 (d, J = 5.7 Hz, 1H), 8.54 (s, 0.5H, FA), 7.88-7.73 (m, 2H),7.66-7.59 (m, 1H), 7.41 (dd, J = 4.4, 2.3 Hz, 1H), 7.32 (ddd, J = 8.1,6.0, 2.1 Hz, 1H), 6.84 (d, J = 7.6 Hz, 2H), 5.10 (dd, J = 6.9, 5.4 Hz,1H), 4.38 (s, 1H), 4.30 (d, J = 4.9 Hz, 3H), 3.95 (d, J = 8.8 Hz, 6H),3.87 (t, J = 4.6 Hz, 4H), 3.71 (d, J = 1.2 Hz, 3H), 3.71-3.56 (m, 2H),3.55-3.37 (m, 3H), 3.33-3.26 (m, 3H), 2.97-2.52 (m, 5H), 2.21-1.92 (m,5H). D122 LCMS: (ESI) m/z: [M + H]⁺ = 793.35; ¹H NMR (400 MHz,Methanol-d4) δ 9.53 (d, J = 2.5 Hz, 1H), 8.68 (dd, J = 5.7, 1.6 Hz, 1H),8.54 (s, 0.6H, FA), 7.85- 7.70 (m, 2H), 7.60 (dd, J = 6.0, 3.1 Hz, 1H),7.42 (dd, J = 3.5, 2.2 Hz, 1H), 7.37-7.29 (m, 1H), 6.84 (d, J = 9.2 Hz,2H), 5.11 (dd, J = 12.5, 5.4 Hz, 1H), 4.40 (s, 1H), 4.31 (dt, J = 6.1,3.1 Hz, 3H), 4.08-4.00 (m, 2H), 3.99- 3.91 (m, 8H), 3.90-3.82 (m, 4H),3.81 (s, 1H), 3.71 (d, J = 1.2 Hz, 3H), 3.68-3.58 (m, 2H), 3.47 (t, J =7.1 Hz, 1H), 2.96-2.81 (m, 1H), 2.74 (dtt, J = 12.1, 6.1, 3.4 Hz, 2H),2.62 (dt, J = 11.5, 5.9 Hz, 2H), 2.25 (t, J = 7.0 Hz, 1H), 2.22-2.05 (m,2H). D123 LCMS: (ESI) m/z: [M + H]⁺ = 807.30 D124 LCMS: (ESI) m/z: [M +H]⁺ = 865.90 D125 LCMS: (ESI) m/z: [M + H]⁺ = 793.20 D126 LCMS: (ESI)m/z: [M + H]⁺ = 793.20 D127 LCMS: (ESI) m/z: [M + H]⁺ = 793.55 D128LCMS: (ESI) m/z: [M + H]⁺ = 779.40 D129 LCMS: (ESI) m/z: [M + H]⁺ =835.70 D130 LCMS: (ESI) m/z: [M + H]⁺ = 851.40 D131 LCMS: (ESI) m/z:[M + H]⁺ = 865.35 D132 LCMS: (ESI) m/z: [M + H]⁺ = 775.3 D133 LCMS:(ESI) m/z: [M + H]⁺ = 777.5 D134 LCMS: (ESI) m/z: [M + H]⁺ = 761.4 D135LCMS: (ESI) m/z: [M + H]⁺ = 763.4 D136 LCMS: (ESI) m/z: [M + H]⁺ = 775.2D137 LCMS: (ESI) m/z: [M + H]⁺ = 789.3 D138 LCMS: (ESI) m/z: [M + H]⁺ =803.5 D139 LCMS: (ESI) m/z: [M + H]⁺ = 805.4 DUO LCMS: (ESI) m/z: [M +H]⁺ = 775.2 D141 LCMS: (ESI) m/z: [M + H]⁺ = 789.3 D142 LCMS: (ESI) m/z:[M + H]⁺ = 803.5 D143 LCMS: (ESI) m/z: [M + H]⁺ = 817.5 D144 LCMS: (ESI)m/z: [M + H]⁺ = 819.3 D145 LCMS: (ESI) m/z: [M + H]⁺ = 689.3 D146 LCMS:(ESI) m/z: [M + H]⁺ = 717.3 D147 LCMS: (ESI) m/z: [M + H]⁺ = 731.4 D148LCMS: (ESI) m/z: [M + H]⁺ = 745.2 D149 LCMS: (ESI) m/z: [M + H]⁺ = 745.3D150 LCMS: (ESI) m/z: [M + H]⁺ = 789.5 D151 LCMS: (ESI) m/z: [M + H]⁺ =805.9 D152 LCMS: (ESI) m/z: [M + H]⁺ = 831.4 D153 LCMS: (ESI) m/z: [M +H]⁺ = 833.3 D154 LCMS: (ESI) m/z: [M + H]⁺ = 789.3 D155 LCMS: (ESI) m/z:[M + H]⁺ = 803.2 D156 LCMS: (ESI) m/z: [M + H]⁺ = 817.6 D157 LCMS: (ESI)m/z: [M + H]⁺ = 831.6 D158 LCMS: (ESI) m/z: [M + H]⁺ = 833.5 D159 LCMS:(ESI) m/z: [M + H]⁺ = 851.25 D160 LCMS: (ESI) m/z: [M + H]⁺ = 821.45D161 LCMS: (ESI) m/z: [M + H]⁺ = 821.35 D162 LCMS: (ESI) m/z: [M + H]⁺ =807.35 D163 LCMS: (ESI) m/z: [M + H]⁺ = 835.50 D164 LCMS: (ESI) m/z:[M + H]⁺ = 821.60 D165 LCMS: (ESI) m/z: [M + H]⁺ = 849.60; ¹H NMR (300MHz, Methanol-d4) δ 9.60- 9.41 (m, 1H), 8.69 (dd, J = 5.6, 3.0 Hz, 1H),8.53 (s, 0.6H, FA), 7.79- 7.50 (m, 3H), 7.44-7.15 (m, 2H), 6.81-6.47 (m,2H), 5.11 (dt, J = 11.6, 4.5 Hz, 1H), 4.57-4.07 (m, 5H), 4.05-3.76 (m,13H), 3.74-3.66 (m, 3H), 3.64-3.44 (m, 1H), 3.05-2.65 (m, 5H), 2.64-2.02(m, 6H). D166 LCMS: (ESI) m/z: [M + H]⁺ = 835.65 D167 LCMS: (ESI) m/z:[M + H]⁺ = 851.25 D168 LCMS: (ESI) m/z: [M + H]⁺ = 851.25 D169 LCMS:(ESI) m/z: [M + H]⁺ = 821.35 D170 LCMS: (ESI) m/z: [M + H]⁺ = 821.35D171 LCMS: (ESI) m/z: [M + H]⁺ = 807.35 D172 LCMS: (ESI) m/z: [M + H]⁺ =835.35 D173 LCMS: (ESI) m/z: [M + H]⁺ = 835.60 D174 LCMS: (ESI) m/z:[M + H]⁺ = 821.65 D175 LCMS: (ESI) m/z: [M + H]⁺ = 849.80 D176 LCMS:(ESI) m/z: [M + H]⁺ = 835.70 D177 LCMS: (ESI) m/z: [M + H]⁺ = 835.65

Example 82—Preparation of Compounds D178-D37

In analogy to the procedures described in the examples above, compoundsD178-D371 were prepared using the appropriate starting materials.

Compound No. LCMS ¹H NMR D178 723.4 ¹H NMR (300 MHz, DMSO-d6) δ 1.55(2H, d), 1.77 (2H, d), 2.03 (3H, d), 2.16 (3H, s), 2.44 (3H, d), 2.73(2H, s), 2.88-3.08 (3H, m), 3.61 (5H, s), 3.80 (6H, s), 4.30 (2H, s),5.12 (1H, m), 6.72 (2H, s), 7.38 (1H, m), 7.48 (1H, d), 7.57 (1H, d),7.80-7.90 (2H, m), 8.23 (1H, s), 8.72 (1H, d), 9.45 (1H, s), 11.12 (1H,s). D179 813.3 ¹H NMR (400 MHz, D .79 (brs, 0.8H, FA(COOH), 11.08 (s,1H), 9.44 (s, 1H), 8.71 (d, J = 5.7 Hz, 1H), 8.14 (s, 0.8H, FA), 7.86(s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 5.8 Hz, 1H), 7.33 (d, J= 2.3 Hz, 1H), 7.24 (dd, J = 8.8, 2.3 Hz, 1H), 7.11 (s, 1H), 6.73 (s,2H), 5.07 (dd, J = 13.0, 5.4 Hz, 1H), 4.08-4.02 (m, 1H), 3.82 (s, 7H),3.69-3.62 (m, 2H), 3.60 (s, 3H), 3.50-3.39 (m, 8H), 3.12- 3.05 (m, 2H),2.95-2.83 (m, 1H), 2.63-2.55 (m, 3H), 2.55 (s, 2H), 2.47-2.39 (m, 3H),2.07-1.98 (m, 1H). D180 788.2 D181 774.7 D182 789.2 ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.21(s, 0.7H, FA), 8.05 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.59-7.54 (m, 1H), 7.31- 7.24 (m, 2H), 6.73 (s, 2H), 5.12 (dd,J = 12.8, 5.4 Hz, 1H), 4.87 (t, J = 6.8 Hz, 1H), 4.14-3.99 (m, 1H), 3.81(s, 6H), 3.66 (s, 2H), 3.61 (s, 3H), 3.44-3.35 (m, 3H), 2.98 (s, 2H),2.92-2.83 (m, 1H), 2.73- 2.55 (m, 4H), 2.44-2.32 (m, 1H), 2.25 (dd, J =18.0, 6.8 Hz, 3H), 2.15-2.00 (m, 3H), 1.95 (td, J = 11.2, 8.4 Hz, 2H).D183 789.5 D184 803.15 D185 715.2 D186 804.65 ¹H NMR (400 MHz, DMSO-d6)δ 11.08 (s, 1H), 9.45 (d, J = 4.3 Hz, 1H), 8.73 (d, J = 5.7 Hz, 1H),8.16 (s, 0.6H, FA), 7.90 (d, J = 6.4 Hz, 1H), 7.64 (dd, J = 8.3, 2.2 Hz,1H), 7.58 (d, J = 5.7 Hz, 1H), 6.90-6.72 (m, 3H), 6.65 (dd, J = 8.5, 2.3Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.57 (d, J = 23.1 Hz, 2H),3.83 (d, J = 18.2 Hz, 6H), 3.74 (s, 4H), 3.60 (d, J = 3.3 Hz, 3H), 2.88(ddd, J = 17.7, 14.0, 5.4 Hz, 1H), 2.72 (s, 1H), 2.65 (s, 2H), 2.62-2.53(m, 4H), 2.44-2.26 (m, 6H), 2.08-1.94 (m, 1H), 1.77 (d, J = 6.5 Hz, 4H),1.53 (s, 4H). D187 790.5 D188 804.6 D189 802.65 D190 788.6 D191 802.55D192 788.8 D193 774.55 D194 774.75 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s,1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.22 (s, 1H, FA), 8.12 (d,J = 7.4 Hz, 1H), 7.88 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 (d, J =5.7 Hz, 1H), 6.74 (d, J = 6.3 Hz, 3H), 6.67-6.56 (m, 1H), 5.06 (dd, J =12.8, 5.4 Hz, 1H), 4.08 (d, J = 10.2 Hz, 3H), 3.97 (s, 2H), 3.82 (s,6H), 3.67 (s, 2H), 3.61 (s, 3H), 3.51 (s, 2H), 3.01 (d, J = 7.1 Hz, 2H),2.95-2.80 (m, 1H), 2.65-2.53 (m, 5H), 2.29 (d, J = 7.6 Hz, 2H), 2.12 (t,J = 10.3 Hz, 2H), 2.07-1.93 (m, 1H). D195 760.5 ¹H NMR (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 9.45 (s, 1H), 8.74 (d, J = 5.6 Hz, 1H), 7.89(s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 5.6 Hz, 1H), 6.82 (d, J= 2.4 Hz, 3H), 6.68 (dd, J = 8.4, 2.1 Hz, 1H), 5.07 (dd, J = 12.9, 5.4Hz, 1H), 4.32 (s, 2H), 4.20 (s, 6H), 4.06 (s, 3H), 3.88 (s, 8H), 3.61(s, 4H), 2.98-2.74 (m, 2H), 2.59 (d, J = 16.5 Hz, 2H), 2.44 (d, J = 7.2Hz, 2H), 2.11-1.95 (m, 1H). D196 757.5 D197 743.35 D198 743.25 D199731.35 ¹H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.52 (s, 1H), 8.77 (d,J = 6.0 Hz, 1H), 8.06 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.85 (dd, J =5.5, 1.6 Hz, 2H), 7.75 (d, J = 6.0 Hz, 1H), 6.87 (s, 2H), 5.16 (dd, J =12.8, 5.4 Hz, 1H), 4.43 (d, J = 13.9 Hz, 1H), 4.29 (s, 2H), 4.14- 4.03(m, 1H), 3.91 (s, 6H), 3.64 (s, 4H), 3.40 (t, J = 8.2 Hz, 2H), 3.18 (m,2H), 3.23-3.13 (m, 2H), 3.02-2.72 (m, 4H), 2.68-2.56 (m, 2H), 2.12-1.99(m, 1H). D200 743.15 D201 804.7 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s,1H), 9.45 (t, J = 1.4 Hz, 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.23 (s, 0.8H,FA), 7.90 (d, J = 6.0 Hz, 1H), 7.76-7.56 (m, 2H), 7.40-7.16 (m, 2H),6.77 (d, J = 10.7 Hz, 2H), 5.17-4.99 (m, 1H), 4.56 (d, J = 19.2 Hz, 2H),3.83 (d, J = 13.5 Hz, 6H), 3.60 (d, J = 2.3 Hz, 3H), 3.43 (s, 6H), 3.01(d, J = 5.0 Hz, 4H), 2.98-2.78 (m, 1H), 2.72 (d, J = 5.9 Hz, 1H), 2.65(s, 2H), 2.63-2.55 (m, 1H), 2.47 (s, 2H), 2.27 (dd, J = 4.3, 2.4 Hz,1H), 2.10-1.91 (m, 1H), 1.73 (d, J = 6.4 Hz, 4H), 1.62-1.47 (m, 2H),1.44-1.26 (m, 2H). D202 818.4 D203 790.6 D204 790.8 D205 776.35 D206776.6 D207 805.65 D208 819.55 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H),9.45 (s, 1H), 8.72 (dd, J = 5.7, 2.2 Hz, 1H), 8.20 (s, 0.6H, FA), 7.90(d, J = 3.6 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.58 (dt, J = 5.7, 1.2Hz, 1H), 7.37- 7.22 (m, 2H), 6.77 (d, J = 9.7 Hz, 2H), 5.12 (dd, J =12.9, 5.4 Hz, 1H), 5.04-4.92 (m, 1H), 4.56 (d, J = 17.5 Hz, 2H), 3.82(d, J = 13.3 Hz, 6H), 3.60 (s, 3H), 2.90 (ddd, J = 17.3, 13.9, 5.4 Hz,1H), 2.71 (s, 1H), 2.61 (d, J = 20.0 Hz, 5H), 2.47-2.22 (m, 9H), 2.06(d, J = 5.9 Hz, 1H), 1.80 (dd, J = 12.2, 6.3 Hz, 2H), 1.70-1.43 (m, 8H).D209 774.6 D210 760.7 D211 743.35 ¹H NMR (400 MHz, DMSO-d6) δ 11.15 (s,1H), 9.44 (s, 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.94-7.79 (m,4H), 7.56 (d, J = 5.7 Hz, 1H), 6.75 (s, 2H), 5.16 (dd, J = 12.8, 5.4 Hz,1H), 3.82 (d, J = 9.2 Hz, 8H), 3.60 (s, 4H), 3.46-3.40 (m, 6H), 2.90(ddd, J = 16.9, 13.8, 5.4 Hz, 1H), 2.70 (s, 2H), 2.66-2.53 (m, 5H), 2.07(ddd, J = 13.3, 5.6, 3.2 Hz, 1H), 1.94 (t, J = 7.0 Hz, 2H), 1.74 (p, J =7.1 Hz, 2H). D212 757.35 D213 771.2 D214 717.35 ¹H NMR (400 MHz,DMSO-d6) δ 11.15 (s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.19(s, 1H FA), 7.87 (d, J = 9.1 Hz, 4H), 7.58 (d, J = 5.6 Hz, 1H), 6.74 (s,2H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 3.81 (s, 6H), 3.60 (s, 6H), 3.47(s, 5H), 2.94-2.85 (m, 1H), 2.68- 2.58 (m, 2H), 2.44 (t, J = 7.2 Hz,6H), 2.12-2.01 (m, 1H), 1.73 (p, J = 7.1 Hz, 2H). D215 729.35 D216703.15 D217 771.15 ¹H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.47 (s,1H), 8.75 (d, J = 5.7 Hz, 1H), 7.97-7.79 (m, 4H), 7.58 (d, J = 5.6 Hz,1H), 6.87 (s, 2H), 5.16 (dd, J = 12.9, 5.3 Hz, 1H), 4.27 (d, J = 4.0 Hz,2H), 4.02 (s, 1H), 3.90 (s, 7H), 3.75 (s, 1H), 3.62 (s, 4H), 3.11 (s,2H), 3.08 (s, 2H), 2.96-2.84 (m, 1H), 2.69 (dd, J = 7.2, 3.6 Hz, 2H),2.66-2.54 (m, 2H), 2.47-2.39 (m, 2H), 2.13-2.00 (m, 3H), 1.92 (t, J =12.4 Hz, 2H). D218 757.35 D219 771.35 ¹H NMR (300 MHz, DMSO-d6) δ 11.15(s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.20 (s, 1H FA),7.97-7.77 (m, 4H), 7.57 (d, J = 5.7 Hz, 1H), 6.74 (s, 2H), 5.24-5.08 (m,1H), 3.82 (s, 6H), 3.71 (s, 3H), 3.61 (s, 4H), 3.11 (s, 4H), 2.98-2.80(m, 2H), 2.76-2.62 (m, 6H), 2.15-2.01 (m, 1H), 1.61 (d, J = 27.8 Hz, 5H)D220 785.15 ¹H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.45 (d, J = 2.0Hz, 1H), 8.73 (dd, J = 5.6, 2.2 Hz, 1H), 7.94-7.87 (m, 2H), 7.84 (q, J =2.9 Hz, 2H), 7.58 (dd, J = 5.7, 2.6 Hz, 1H), 6.74 (s, 2H), 5.16 (dd, J =12.8, 5.4 Hz, 1H), 3.82 (s, 6H), 3.60 (d, J = 1.4 Hz, 5H), 3.52 (t, J =7.0 Hz, 1H), 3.17 (s, 2H), 2.89 (ddd, J = 16.6, 13.6, 5.4 Hz, 1H), 2.70(t, J = 7.0 Hz, 2H), 2.66-2.56 (m, 7H), 2.41 (s, 2H), 2.12- 2.00 (m,1H), 1.76 (t, J = 7.1 Hz, 1H), 1.67 (t, J = 7.2 Hz, 1H), 1.49 (s, 4H).D221 817.35 ¹H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (s, 1H),8.73 (d, J = 5.7 Hz, 1H), 8.20 (s, 1H, FA), 7.92-7.80 (m, 2H), 7.60 (d,J = 5.7 Hz, 1H), 7.38-7.21 (m, 2H), 6.74 (s, 2H), 5.12 (dd, J = 12.9,5.4 Hz, 1H), 5.03 (t, J = 6.9 Hz, 1H), 3.81 (s, 6H), 3.61 (s, 3H), 3.58(s, 2H), 3.44 (s, 4H), 2.96-2.82 (m, 3H), 2.66-2.54 (m, 5H), 2.21- 1.98(m, 3H), 1.93-1.81 (m, 2H), 1.66-1.43 (m, 8H). D222 776.4 D223 776.35D224 790.4 D225 776.35 D226 762.8 D227 748.3 ¹H NMR (300 MHz, DMSO-d6) δ11.07 (s, 1H), 9.44 (s, 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.17 (s, 0.6H,FA), 7.88 (s, 1H), 7.59 (dd, J = 9.7, 7.0 Hz, 2H), 6.76 (d, J = 7.3 Hz,3H), 6.61 (d, J = 8.4 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.87 (t,J = 5.4 Hz, 1H), 4.15-3.95 (m, 2H), 3.84 (s, 6H), 3.67 (d, J = 15.2 Hz,3H), 3.60 (s, 3H), 3.11- 2.71 (m, 2H), 2.66-2.55 (m, 5H), 2.27 (s, 3H),2.12-1.88 (m, 4H), 1.75 (d, J = 10.1 Hz, 1H), 1.64-1.36 (m, 4H). D228791.55 D229 751.2 D230 791.4 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H),9.45 (t, J = 1.2 Hz, 1H), 8.73 (dd, J = 5.7, 1.0 Hz, 1H), 8.19 (s, 0.3H,FA), 7.99-7.73 (m, 2H), 7.66-7.50 (m, 1H), 7.39-7.22 (m, 2H), 6.77 (d, J= 9.5 Hz, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.87 (t, J = 6.8 Hz,1H), 4.56 (d, J = 19.1 Hz, 2H), 3.82 (d, J = 13.1 Hz, 6H), 3.60 (d, J =1.5 Hz, 3H), 3.26 (s, 2H), 3.17 (s, 2H), 2.89 (s, 1H), 2.78-2.61 (m,6H), 2.61-2.52 (m, 2H), 2.48-2.33 (m, 2H), 2.28 (dd, J = 3.8, 1.9 Hz,1H), 2.19 (dd, J = 11.7, 8.0 Hz, 2H), 2.04 (d, J = 11.6 Hz, 1H), 1.53(d, J = 7.9 Hz, 2H), 1.42-1.19 (m, 2H). D231 774.2 D232 774.4 D233 735.2¹H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (d, J = 0.8 Hz, 1H),8.72 (d, J = 5.7 Hz, 1H), 8.18 (s, 0.5H, FA), 7.93-7.79 (m, 2H), 7.56(dd, J = 5.7, 0.9 Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 6.74 (s, 2H), 5.27(s, 1H), 5.14 (dd, J = 12.9, 5.3 Hz, 1H), 4.63 (t, J = 8.1 Hz, 1H), 4.34(dd, J = 10.5, 6.5 Hz, 1H), 4.13 (d, J = 8.3 Hz, 1H), 3.82 (s, 7H), 3.73(s, 2H), 3.60 (s, 3H), 3.50 (d, J = 9.7 Hz, 2H), 3.07 (s, 2H), 2.98-2.80(m, 1H), 2.71-2.53 (m, 3H), 2.38 (d, J = 7.5 Hz, 2H), 2.17-1.97 (m, 1H).D234 775.35 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H),8.73 (dd, J = 5.7, 1.2 Hz, 1H), 8.20 (s, 1H, FA), 7.96-7.76 (m, 2H),7.69-7.54 (m, 1H), 7.42-7.19 (m, 2H), 6.75 (d, J = 1.7 Hz, 2H), 5.12(dd, J = 12.9, 5.3 Hz, 1H), 4.90 (t, J = 6.7 Hz, 1H), 4.14 (d, J = 27.9Hz, 2H), 3.92 (s, 1H), 3.83 (d, J = 2.2 Hz, 7H), 3.75 (s, 2H), 3.61 (s,3H), 3.49 (t, J = 6.8 Hz, 3H), 3.08 (s, 2H), 2.99-2.70 (m, 4H),2.68-2.55 (m, 3H), 2.40-2.19 (m, 4H), 2.15-1.94 (m, 1H). D235 729.3 D236715.15 D237 689.2 D238 743.4 D239 729.35 D240 757.35 D241 729.15 D242729.2 D243 757.35 D244 791.23 D245 762.4 D246 791.4 D247 790.4 D248762.3 D249 723.3 D250 762.4 D251 763.6 ¹H NMR (400 MHz, DMSO-d6) δ 11.12(s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.21 (s, 1.4H, FA),7.88 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.28(d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.3, 2.3 Hz, 1H), 6.75 (s, 2H), 5.12(dd, J = 12.8, 5.4 Hz, 1H), 4.90-4.80 (m, 1H), 3.82 (s, 6H), 3.61 (d, J= 3.2 Hz, 5H), 3.36 (s, 2H), 3.27 (s, 2H), 2.89 (ddd, J = 16.7, 13.7,5.3 Hz, 1H), 2.75- 2.56 (m, 4H), 2.45 (q, J = 7.1, 6.7 Hz, 4H),2.26-2.13 (m, 5H), 2.11-1.98 (m, 1H), 1.50 (t, J = 7.2 Hz, 2H), 1.32 (t,J = 7.2 Hz, 2H). D252 762.4 D253 777.35 D254 748.4 D255 790.25 D256818.2 D257 777.7 D258 790.4 D259 777.2 D260 805.35 D261 819.2 D262819.25 D263 805.35 D264 803.2 D265 803.15 D266 789.3 D267 789.3 D268715.3 D269 757.35 D270 719.35 D271 719.28 ¹H NMR (400 MHz, DMSO-d6) δ11.03 (s, 1H), 9.42 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.91 (s, 1H),7.85 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 5.7 Hz, 1H), 6.80(s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 6.62 (dd, J = 8.4, 2.1 Hz, 1H), 5.53(s, 2H), 5.02 (dd, J = 12.8, 5.4 Hz, 1H), 4.57 (td, J = 6.3, 3.2 Hz,1H), 4.53 (s, 2H), 4.24-4.15 (m, 2H), 3.86 (s, 6H), 3.79 (dd, J = 9.7,3.9 Hz, 2H), 3.56 (s, 3H), 3.15 (d, J = 5.3 Hz, 1H), 2.85 (ddd, J =16.8, 13.8, 5.3 Hz, 1H), 2.60- 2.50 (m, 2H), 2.05 (s, 1H), 2.03-1.94 (m,1H). D272 747.28 D273 720.03 D274 735.52 D275 765.06 D276 776.47 D277776.33 D278 804.19 D279 761.28 ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 9.43 (s, 1H), 8.71 (d, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.86 (s, 1H),7.82 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.45 (d, J = 2.3 Hz,1H), 7.35 (dd, J = 8.4, 2.3 Hz, 1H), 6.76 (s, 2H), 5.09 (dd, J = 12.9,5.4 Hz, 1H), 4.41 (t, J = 6.6 Hz, 2H), 3.83 (s, 5H), 3.59 (s, 2H), 3.15(d, J = 5.1 Hz, 1H), 3.11 (d, J = 6.4 Hz, 1H), 2.87 (ddd, J = 17.2,13.9, 5.3 Hz, 1H), 2.70-2.51 (m, 2H), 2.03 (d, J = 15.9 Hz, 5H). D280802.16 D281 830.16 D282 735.45 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s,1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.47 (d, J =2.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 6.71 (s, 2H), 5.26 (s, 2H),4.40 (s, 1H), 3.78 (s, 5H), 3.55 (s, 3H), 2.88 (ddd, J = 18.2, 13.8, 5.4Hz, 1H), 2.71- 2.53 (m, 2H), 2.38-2.24 (m, 2H), 2.09 (d, J = 28.1 Hz,4H). D283 749.31 D284 779.27 D285 790.33 D286 790.4 ¹H NMR (400 MHz,DMSO-d6) δ 11.03 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.3Hz, 1H), 6.72 (s, 2H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.55 (s, 2H),4.20 (dd, J = 9.2, 6.3 Hz, 2H), 3.80 (s, 6H), 3.58 (s, 2H), 2.97-2.72(m, 0H), 2.18 (s, 1H), 2.05 (s, 1H), 2.02-1.94 (m, 1H). D287 818.26 D288765.27 D289 747.35 D290 791.24 D291 802.37 D292 779.2 D293 809.16 D294820.29 D295 820.08 D296 847.22 D297 719.28 D298 733.49 D299 763.31 D300774.44 D301 774.02 D302 802.58 D303 708.22 D304 803.4 ¹H NMR (400 MHz,Methanol-d4) δ 9.58 (s, 1H), 8.70 (d, J = 6.0 Hz, 1H), 7.91 (d, J = 2.2Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.31 (d, J= 2.3 Hz, 1H), 7.26 (dd, J = 8.3, 2.3 Hz, 1H), 6.89 (s, 2H), 5.13 (dd, J= 12.6, 5.4 Hz, 1H), 4.98 (t, J = 6.5 Hz, 1H), 4.43 (s, 2H), 3.98 (d, J= 4.3 Hz, 6H), 3.74 (s, 3H), 3.70- 3.50 (m, 4H), 3.33-2.94 (m, 6H),2.93-2.66 (m, 4H), 2.56 (s, 1H), 2.27 (s, 1H), 2.17-1.95 (m, 10H), 1.67(q, J = 12.6 Hz, 1H). D305 789.7 ¹H NMR (400 MHz, Methanol-d4) δ 9.54(s, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.50 (s, 2H, FA), 7.83 (d, J = 8.3Hz, 1H), 7.75 (s, 1H), 7.62 (d, J = 5.7 Hz, 1H), 7.31 (d, J = 2.2 Hz,1H), 7.26 (dd, J = 8.3, 2.2 Hz, 1H), 6.82 (s, 2H), 5.13 (dd, J = 12.5,5.4 Hz, 1H), 5.01- 4.97 (m, 1H), 4.17 (s, 2H), 3.95 (s, 6H), 3.77-3.65(m, 5H), 3.56- 3.40 (m, 5H), 3.28 (s, 1H), 3.07-2.92 (m, 3H), 2.91-2.84(m, 1H), 2.81-2.65 (m, 4H), 2.50-2.40 (m, 1H), 2.18-2.07 (m, 6H),2.05-1.96 (m, 2H). D306 715.3 ¹H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H),9.45 (s, 1H), 8.72 (d, J = 5.6 Hz, 1H), 8.18 (s, 1H FA), 7.89 (d, J =17.4 Hz, 4H), 7.56 (d, J = 5.6 Hz, 1H), 6.74 (s, 2H), 5.17 (dd, J =12.8, 5.4 Hz, 1H), 3.82 (s, 6H), 3.74 (s, 2H), 3.63 (d, J = 19.3 Hz,6H), 3.27 (s, 3H), 2.90 (ddd, J = 16.8, 13.7, 5.3 Hz, 1H), 2.78 (s, 2H),2.66-2.57 (m, 3H), 2.55 (s, 1H), 2.11-2.02 (m, 1H), 1.96 (t, J = 6.9 Hz,2H). D307 729.3 ¹H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.45 (s, 1H),8.72 (d, J = 5.7 Hz, 1H), 7.99-7.80 (m, 4H), 7.56 (d, J = 5.7 Hz, 1H),6.73 (s, 2H), 5.16 (dd, J = 12.7, 5.4 Hz, 1H), 3.82 (s, 6H), 3.71 (s,2H), 3.60 (s, 3H), 3.53 (s, 2H), 3.10 (s, 4H), 2.90 (ddd, J = 16.7,13.6, 5.4 Hz, 1H), 2.65-2.54 (m, 1H), 2.44 (s, 5H), 2.12-2.01 (m, 1H),1.67 (t, J = 5.5 Hz, 4H). D308 743.35 D309 701.3 D310 743.55 D311 743.3D312 757.3 D313 771.45 D314 743.3 D315 743.3 D316 717.3 D317 729.3 D318757.3 D319 761.35 D320 761.28 D321 763.24 D322 747.42 D323 746.83 D324746.55 D325 747.33 D326 747.45 D327 706.67 D328 779.84 ¹H NMR (400 MHz,DMSO-d6) δ 11.04 (s, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.25 (d, J = 2.7 Hz,1H), 8.19 (s, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H),7.22 (dd, J = 8.6, 2.3 Hz, 1H), 6.85 (d, J = 5.6 Hz, 2H), 5.04 (dd, J =12.9, 5.4 Hz, 1H), 3.83 (d, J = 2.7 Hz, 7H), 3.59 (s, 3H), 3.48 (d, J =5.0 Hz, 2H), 3.39 (t, J = 5.0 Hz, 4H), 2.81 (dd, J = 25.4, 11.4 Hz, 3H),2.63-2.51 (m, 2H), 2.32-2.22 (m, 2H), 2.06-1.90 (m, 1H), 1.56 (s, 1H),1.34 (d, J = 7.5 Hz, 2H), 1.09 (s, 1H) D329 725.87 ¹H NMR (400 MHz,DMSO-d6) δ 11.04 (s, 1H), 8.24-8.12 (m, 2H), 8.03 (d, J = 2.6 Hz, 1H),7.88-7.72 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H),7.22 (dd, J = 8.6, 2.3 Hz, 1H), 6.79 (s, 2H), 3.83 (s, 6H), 3.57 (s,2H), 3.51 (s, 3H), 3.40 (t, J = 5.1 Hz, 4H), 2.91-2.78 (m, 3H),2.66-2.50 (m, 2H), 2.36-2.24 (m, 2H), 2.14 (t, J = 11.6 Hz, 2H), 2.08(s, 3H), 1.99 (ddd, J = 11.5, 6.0, 3.7 Hz, 1H), 1.61 (d, J = 12.4 Hz,2H), 1.35 (q, J = 7.0 Hz, 2H), 1.26 (s, 2H), 1.13 (q, J = 11.2, 10.7 Hz,2H). D330 614.68 ¹H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.15 (s,1H), 8.02 (d, J = 2.7 Hz, 1H), 7.79 (dd, J = 2.8, 1.3 Hz, 1H), 7.63 (d,J = 8.5 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.7, 2.3 Hz,1H), 6.80 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 3.84 (s, 6H), 3.55(s, 2H), 3.37 (t, J = 5.1 Hz, 4H), 2.66-2.53 (m, 2H), 2.08 (s, 3H). D331654.74 ¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.12 (s, 1H), 8.04 (d,J = 2.6 Hz, 1H), 7.80 (dd, J = 2.7, 1.3 Hz, 1H), 7.61 (d, J = 8.3 Hz,1H), 6.82 (s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 5.02 (dd, J = 12.9, 5.4 Hz,1H), 3.85 (s, 6H), 3.72 (s, 5H), 3.52 (s, 3H), 2.93-2.74 (m, 1H), 2.08(s, 3H), 1.98 (dd, J = 9.2, 4.2 Hz, 1H), 1.76 (s, 5H). D332 669.75 D333724.79 D334 594.73 ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.13 (s,1H), 8.05 (d, J = 2.7 Hz, 1H), 7.80 (dd, J = 2.8, 1.3 Hz, 1H), 6.82 (s,2H), 5.73 (s, 1H), 3.85 (s, 6H), 3.71 (s, 2H), 3.52 (s, 3H), 3.08-2.85(m, 4H), 2.79-2.53 (m, 3H), 2.38-2.28 (m, 3H), 2.08 (s, 3H), 1.86-1.74(m, 1H), 1.65 (d, J = 12.7 Hz, 2H), 1.33 (s, 3H), 1.27-1.12 (m, 3H).D335 609.66 D336 654.74 D337 640.72 D338 640.72 D339 626.69 D340 679.75¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.03 (s, 1H), 8.14 (d, J =1.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.34 (t, J = 2.8Hz, 1H), 6.82 (s, 2H), 6.75 (d, J = 2.1 Hz, 1H), 6.62 (dd, J = 8.4, 2.2Hz, 1H), 6.54 (t, J = 2.4 Hz, 1H), 5.73 (s, 1H), 5.02 (dd, J = 12.9, 5.4Hz, 1H), 3.83 (s, 6H), 3.71 (s, 4H), 3.58 (s, 3H), 3.53 (s, 2H), 2.86(ddd, J = 17.3, 13.9, 5.4 Hz, 1H), 2.64-2.50 (m, 1H), 1.98 (dd, J = 9.2,4.0 Hz, 1H), 1.72 (d, J = 5.8 Hz, 4H). D341 690.72 ¹H NMR (400 MHz,DMSO-d6) δ 8.13 (dd, J = 9.6, 2.7 Hz, 2H), 6.83 (d, J = 0.9 Hz, 2H),11.03 (s, 1H), 8.37 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H),6.78-6.71 (m, 1H), 6.62 (dd, J = 8.4, 2.1 Hz, 1H), 5.02 (dd, J = 12.9,5.4 Hz, 1H), 3.84 (d, J = 0.8 Hz, 6H), 3.69 (s, 4H), 3.57 (s, 3H), 3.50(d, J = 4.1 Hz, 2H), 2.86 (ddd, J = 17.3, 13.9, 5.4 Hz, 1H), 2.38 (s,5H), 1.69 (s, 4H). D342 712.15 ¹H NMR (400 MHz, DMSO-d6) δ 11.07 (s,1H), 9.04 (d, J = 3.3 Hz, 1H), 8.66 (d, J = 3.4 Hz, 1H), 8.20 (s, 1H,FA), 7.64 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H),6.88 (s, 2H), 5.06 (dd, J = 13.0, 5.3 Hz, 1H), 4.02 (d, J = 12.8 Hz,2H), 3.84 (s, 6H), 3.57- 3.47 (m, 5H), 2.91 (dt, J = 22.4, 13.1 Hz, 3H),2.71-2.55 (m, 2H), 2.42-2.23 (m, 10H), 2.09-1.93 (m, 1H), 1.82-1.68 (m,2H), 1.64-1.50 (m, 1H), 1.39-1.30 (m, 2H), 1.22-1.09 (m, 2H). D343 628.5¹H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.47 (s, 1H, TFA), 7.77 (d, J= 8.5 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.38-7.23 (m, 2H), 6.69 (s,2H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 4.33 (s, 2H), 4.18 (d, J = 12.1Hz, 2H), 3.89 (s, 6H), 3.55 (s, 4H), 3.53-3.45 (m, 5H), 2.99-2.81 (m,1H), 2.60 (d, J = 18.3 Hz, 2H), 2.35 (s, 3H), 2.05 (s, 4H). D344 600.2¹H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H),8.14 (s, 1H FA), 7.97-7.88 (m, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.32 (d, J= 2.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.85 (s, 2H), 6.50 (d, J = 9.4 Hz,1H), 5.10-5.00 (m, 1H), 3.87 (s, 6H), 3.67 (s, 2H), 3.53 (s, 3H), 3.44(d, 5H). 2.97-2.78 (m, 1H), 2.67-2.60 (m, 5H), 2.58-2.52 (m, 1H),2.09-1.92 (m, 1H). D345 737.3 ¹H NMR (300 MHz, Methanol-d4) δ 8.31 (s,1H FA), 7.65 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 6.84 (d, J = 2.1 Hz,1H), 6.72-6.63 (m, 3H), 5.07 (dd, J = 12.4, 5.4 Hz, 1H), 4.48 (s, 2H),4.25 (s, 2H), 4.06- 3.90 (m, 8H), 3.82 (s, 4H), 3.58 (d, J = 20.8 Hz,4H), 2.97-2.66 (m, 5H), 2.63 (s, 3H), 2.27-2.03 (m, 8H), 1.95 (s, 4H).D346 737.7 ¹H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.16 (s, 1H, FA),7.64 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 6.77 (d, J = 2.1 Hz,1H), 6.69-6.53 (m, 3H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 3.92- 3.85 (m,2H), 3.82 (s, 6H), 3.74 (s, 4H), 3.71-3.61 (m, 2H), 3.54 (s, 4H),2.98-2.78 (m, 2H), 2.71-2.54 (m, 2H), 2.54-2.50 (m, 2H), 2.48-2.42 (m,3H), 2.37-2.20 (m, 4H), 2.11-1.93 (m, 4H), 1.82-1.65 (m, 4H), 1.20 (d, J= 26.6 Hz, 1H). D347 709.2 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H),8.23 (s, 1H), 8.17 (s, 1H, FA), 7.94 (d, J = 9.6 Hz, 1H), 7.64 (d, J =8.3 Hz, 1H), 6.86 (d, J = 4.5 Hz, 2H), 6.77 (d, J = 2.1 Hz, 1H), 6.64(dd, J = 8.4, 2.2 Hz, 1H), 6.50 (d, J = 9.4 Hz, 1H), 5.05 (dd, J = 12.9,5.3 Hz, 1H), 3.88 (t, J = 2.1 Hz, 7H), 3.79 (s, 2H), 3.73 (s, 5H), 3.54(s, 6H), 3.19 (d, J = 29.3 Hz, 1H), 2.99-2.81 (m, 1H), 2.58 (d, J = 16.2Hz, 2H), 2.44 (s, 2H), 2.28 (s, 3H), 2.01 (d, J = 12.4 Hz, 1H), 1.73 (s,4H). D348 749.25 ¹H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J = 2.6 Hz, 1H),7.88 (t, J = 1.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 2.1 Hz,2H), 6.77 (d, J = 2.2 Hz, 1H), 6.66 (m, J = 8.3, 2.0 Hz, 1H), 6.09-5.91(m, 1H), , 5.19 (m, J = 10.3, 1.5 Hz, 1H), 5.14-4.98 (m, 2H), 4.62 (d, J= 5.4 Hz, 2H), 4.34 (d, J = 16.5 Hz, 2H), 4.18 (s, 2H), 3.99 (d, J =10.2 Hz, 2H), 3.92 (s, 6H), 3.87 (s, 2H), 3.81 (s, 2H), 3.41 (d, J = 6.6Hz, 4H), 3.17 (d, J = 8.1 Hz, 1H), 2.94 (s, 3H), 2.89-2.78 (m, 1H),2.65-2.54 (m, 1H), 2.40-2.23 (m, 1H), 2.11 (s, 4H), 2.06- 1.83 (m, 3H).D349 723.2 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.78 (s, 2H, TFA),7.69 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 6.75 (dd, J = 21.5, 3.2 Hz, 3H),6.66 (dd, J = 8.3, 2.4 Hz, 1H), 6.38 (s, 1H), 5.06 (dd, J = 12.9, 5.4Hz, 1H), 4.39 (s, 1H), 4.34 (d, J = 5.5 Hz, 1H), 4.22 (s, 2H), 4.01 (d,J = 8.8 Hz, 2H), 3.89 (s, 8H), 3.82 (s, 2H), 3.46 (s, 5H), 3.25-3.08 (m,2H), 3.03-2.82 (m, 3H), 2.64-2.59 (m, 2H), 2.21- 2.09 (m, 5H), 2.09-1.77(m, 4H). D350 795.4 ¹H NMR (300 MHz, MeOD) δ 8.04 (d, 1H), 7.82 (d, 1H),7.67 (d, 1H), 6.95-6.84 (m, 3H), 6.71 (dd, 1H), 5.08 (dd, 1H), 4.58-4.45(m, 2H), 4.34 (t, 2H), 4.24 (s, 2H), 4.17-4.09 (m, 2H), 4.01 (s, 6H),3.94-3.86 (m, 4H), 3.69 (s, 3H), 3.55-3.49 (m, 5H), 3.20-3.03 (m, 2H),2.91-2.77 (m, 2H), 2.72 (s, 4H), 2.35-2.00 (m, 5H). D351 748.7 ¹H NMR(400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.94 (br s, 2H, TFA salt), 8.07 (s,1H), 7.69 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 3.7 Hz, 3H), 6.66 (dd, J =8.4, 2.3 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.40 (s, 1H), 4.35(d, J = 5.6 Hz, 1H), 4.27-4.16 (m, 2H), 4.03 (q, J = 8.7, 7.5 Hz, 2H),3.88 (s, 8H), 3.82 (s, 2H), 3.55 (s, 3H), 3.39 (s, 5H), 3.18 (s, 1H),3.04-2.82 (m, 3H), 2.64-2.54 (m, 2H), 2.36 (s, 3H), 2.15 (d, J = 14.0Hz, 2H), 2.02 (dd, J = 9.7, 4.6 Hz, 1H), 1.97- 1.84 (m, 2H). D352 734.45¹H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.69 (s, 1H),8.14 (s, 0.4H, FA), 7.67 (d, J = 8.3 Hz, 1H), 7.02 (s, 2H), 6.77 (s,1H), 6.65 (d, J = 8.4 Hz, 1H), 5.05 (dd, J = 12.6, 5.4 Hz, 1H), 4.30 (s,2H), 4.14 (s, 3H), 3.95 (s, 7H), 3.91-3.78 (m, 6H), 3.63 (s, 4H),2.96-2.80 (m, 2H), 2.97-2.79 (m, 5H), 2.05-1.79 (m, 5H). D353 723.5 ¹HNMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.16 (s, 1H FA), 7.72 (d, J =2.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 2.7, 1.2 Hz, 1H),6.99 (s, 1H), 6.88 (s, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.5,2.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.78 (s, 3H), 3.74 (d, J =2.8 Hz, 7H), 3.60 (s, 2H), 3.49 (s, 6H), 2.90 (s, 3H), 2.73-2.58 (m,5H), 2.39-2.19 (m, 3H), 2.05 (s, 3H), 2.02 (d, J = 7.1 Hz, 1H), 1.74 (s,4H). D354 737.45 ¹H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 2H FA), 7.64(d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 6.83 (d,J = 2.0 Hz, 1H), 6.67 (dd, J = 8.3, 2.0 Hz, 1H), 5.07 (dd, J = 12.4, 5.5Hz, 1H), 4.43 (s, 2H), 4.26 (s, 2H), 4.03 (s, 2H), 3.91 (s, 3H), 3.83(s, 4H), 3.79 (s, 3H), 3.60 (s, 3H), 3.29 (s, 1H), 3.03 (s, 2H),2.95-2.64 (m, 7H), 2.16 (s, 3H), 2.15-2.07 (m, 1H), 2.07-1.87 (m, 7H).D355 809.5 ¹H NMR (300 MHz, MeOD) δ 8.07 (d, 1H), 7.74-7.63 (m, 2H),6.88 (d, 3H), 6.71 (dd, 1H), 5.08 (dd, 1H), 4.58-4.45 (m, 2H), 4.41-4.28 (m, 4H), 4.19-4.07 (m, 2H), 4.01 (s, 6H), 3.98-3.82 (m, 4H), 3.70(s, 3H), 3.58-3.41 (m, 5H), 3.18-3.02 (m, 2H), 2.98 (s, 3H), 2.93-2.79(m, 2H), 2.76 (s, 3H), 2.77-2.66 (m, 1H), 2.40- 2.01 (m, 5H). D356 745.5¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.93 (br s, 2H, TFA salt),8.36 (d, J = 8.0 Hz, 1H), 7.78-7.53 (m, 4H), 7.41 (d, J = 8.5 Hz, 1H),6.85 (s, 2H), 6.70 (s, 2H), 5.07 (dd, J = 13.2, 4.9 Hz, 1H), 4.50-3.96(m, 8H), 3.90 (s, 6H), 3.78-3.55 (m, 8H), 3.53-3.49 (m, 1H), 3.28-3.12(m, 2H), 3.09-2.82 (m, 3H), 2.75-2.56 (m, 1H), 2.43-2.24 (m, 2H),2.19-1.83 (m, 5H) D357 641.748028 D358 641.748028 D359 737.4 ¹H NMR (300MHz, DMSO-d6) δ 11.10 (s, 1H), 10.32-9.43 (m, 2H), 7.69 (d, J = 8.3 Hz,1H), 7.22-7.05 (m, 2H), 6.92 (s, 1H), 6.83-6.74 (m, 1H), 6.66 (dd, J =8.2, 2.1 Hz, 1H), 5.17-4.99 (m, 1H), 4.57-4.33 (m, 2H), 4.34-4.15 (m,2H), 4.15-3.94 (m, 2H), 3.90 (s, 2H), 3.82 (s, 6H), 3.73 (m, 3H), 3.52(s, 4H), 3.25-3.10 (m, 2H), 3.08-2.79 (m, 4H), 2.62 (m, 2H), 2.59-2.54(m, 1H), 2.54-2.41 (m, 1H), 2.23-2.06 (m, 3H), 2.02 (s, 4H), 2.00-1.83(m, 2H). D360 745.6 ¹H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.83 (brs, 2H, TFA salt), 8.36 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H),7.66-7.48 (m, 4H), 6.85 (s, 2H), 6.55-6.44 (m, 2H), 5.04 (dd, J = 13.2,4.8 Hz, 1H), 4.40 (t, J = 13.8 Hz, 2H), 4.32-4.13 (m, 4H), 4.05 (s, 2H),3.90 (s, 6H), 3.81-3.65 (m, 5H), 3.60 (s, 4H), 3.55-3.50 (m, 2H), 3.20(s, 1H), 3.10-2.80 (m, 3H), 2.62 (s, 1H), 2.41-2.24 (m, 1H), 2.19-2.05(m, 2H), 2.02-1.82 (m, 3H). D361 735.4 ¹H NMR (400 MHz, DMSO-d6) δ 8.33(s, 1H), 8.14 (s, FA, 1H), 7.91 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.13(s, 1H), 7.03 (s, 2H), 6.73-6.67 (m, 2H), 5.06 (dd, J = 13.2, 5.1 Hz,1H), 4.34 (s, J = 16.7 Hz, 3H), 4.30 (d, J = 16.7 Hz, 1H) 4.19 (d, J =16.7 Hz, 1H), 4.14 (m, 2H), 3.92 (s, 6H), 3.90-3.80 (m, 2H), 3.63 (s,4H), 3.06 (s, 2H), 2.96-2.82 (m, 3H), 2.74-2.56 (m, 3H), 2.45-2.32 (m,2H), 2.01-1.92 (m, 2H), 1.87 (s, 5H). D362 725.3 ¹H NMR (400 MHz,DMSO-d6) δ 10.95 (s, 1H), 8.17 (s, 1H, FA), 7.55-7.46 (m, 2H), 7.04 (s,2H), 6.54 (s, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.12 (m, 2H),3.85 (d, J = 12.7 Hz, 2H), 3.77 (s, 6H), 3.53 (s, 2H), 3.46 (s, 3H),2.97-2.74 (m, 3H), 2.61 (s, 1H), 2.47-2.28 (m, 11H), 2.06 (d, J = 2.7Hz, 6H), 1.97 (s, 1H), 1.73 (d, J = 12.6 Hz, 2H), 1.50 (s, 1H), 1.36 (d,J = 7.5 Hz, 2H), 1.26-1.13 (m, 2H). D363 735.6 ¹H NMR (400 MHz, DMSO-d6)δ 10.94 (s, 1H), 8.33 (s, 1H), 8.22 (s, FA, 1H), 7.89 (s, 1H), 7.48 (d,J = 8.3 Hz, 1H), 7.11 (s, 1H), 6.92 (s, 2H), 6.53-6.43 (t, 2H), 5.03(dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.17 (d, J = 16.9Hz, 1H), 3.85 (s, 6H), 3.67 (s, 2H), 3.61 (s, J = 6.9 Hz, 6H), 3.47 (s,J = 6.9 Hz, 4H), 2.98 (m, J = 6.9 Hz, 4H), 2.60 (s, 1H), 2.46-2.34 (m,3H), 2.28 (s, 3H), 1.99- 1.89 (m, 1H), 1.72 (t, J = 5.2 Hz, 4H). D364781.2 ¹H NMR (300 MHz, MeOD) δ 8.05 (d, J = 2.5 Hz, 1H), 7.83 (s, 1H),7.41 (d, J = 8.2 Hz, 1H), 6.95-6.84 (m, 3H), 6.79 (d, J = 8.2 Hz, 1H),5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.51-1.45 (m, 2H), 4.44- 4.30 (m, 4H),4.25 (s, 2H), 4.14 (s, 2H), 4.01 (s, 6H), 3.79-3.73 (m, 4H), 3.69 (s,3H), 3.55-3.48 (m, 4H), 3.18-3.04 (m, 2H), 3.00- 2.78 (m, 2H), 2.72 (s,3H), 2.60-2.41 (m, 1H), 2.28-2.12 (m, 5H), 1.38-1.28 (m, 2H). D365735.45 ¹H NMR (400 MHz, MeOD) δ 8.48 (s, FA, 1H), 7.93 (d, J = 1.6 Hz,1H), 7.77 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H),7.25 (s, 2H), 6.85 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.3, 2.2 Hz, 1H),5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.48 (s, 2H), 4.45-4.33 (m, 2H), 4.23(s, 735.452H), 4.02 (s, 6H), 3.97 (s, 2H), 3.72 (s, 3H), 3.67 (s, 4H),3.43-3.35 (m, 1H), 3.22-3.01 (m, 1H), 2.96-2.85 (m, 1H), 2.84-2.75 (m,1H), 2.74 (s, 2H), 2.64-2.42 (m, 5H), 2.23-2.13 (m, 1H), 1.91 (s, 4H).D366 790.2 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.56 (d, J = 5.4Hz, 1H), 9.29 (s, 2H, TFA), 8.39 (d, J = 5.4 Hz, 1H), 8.08 (s, 1H), 7.64(dd, J = 8.4, 3.2 Hz, 1H), 7.17-7.04 (m, 3H), 7.02-6.95 (m, 1H), 5.08(dd, J = 13.3, 5.1 Hz, 1H), 4.88 (p, J = 6.7 Hz, 1H), 4.43- 4.14 (m,4H), 3.90 (s, 6H), 3.65 (s, 3H), 3.47-3.15 (m, 4H), 3.09- 2.78 (m, 7H),2.60 (d, J = 16.2 Hz, 2H), 2.46-2.34 (m, 2H), 2.17- 2.08 (m, 1H),1.98-1.87 (m, 6H), 1.86-1.82 (m, 3H), 1.49 (q, J = 12.7 Hz, 2H). D367790.5 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.56 (d, J = 5.4 Hz,1H), 9.29 (s, 2H, TFA), 8.39 (d, J = 5.4 Hz, 1H), 8.08 (s, 1H), 7.64(dd, J = 8.4, 3.2 Hz, 1H), 7.17-7.04 (m, 3H), 7.02-6.95 (m, 1H), 5.08(dd, J = 13.3, 5.1 Hz, 1H), 4.88 (p, J = 6.7 Hz, 1H), 4.43- 4.14 (m,4H), 3.90 (s, 6H), 3.65 (s, 3H), 3.47-3.15 (m, 4H), 3.09- 2.78 (m, 7H),2.60 (d, J = 16.2 Hz, 2H), 2.46-2.34 (m, 2H), 2.17- 2.08 (m, 1H),1.98-1.87 (m, 6H), 1.86-1.82 (m, 3H), 1.49 (q, J = 12.7 Hz, 2H). D368790.65 ¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.75 (s, 1H), 9.55 (s,1H), 9.32 (br s, 1H, TFA salt), 8.20 (s, 1H), 7.52 (dd, J = 8.4, 2.7 Hz,1H), 7.19-7.09 (m, 2H), 6.97 (s, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H),4.93-4.85 (m, 1H), 4.38 (d, J = 16.9 Hz, 2H), 4.26 (d, J = 16.9 Hz, 2H),3.92 (s, 6H), 3.68 (s, 3H), 3.54-3.38 (m, 4H), 3.25- 3.21 (m, 1H),3.06-2.82 (m, 6H), 2.67-2.56 (m, 2H), 2.44-2.38 (m, 2H), 2.18-1.73 (m,10H), 1.54-1.46 (m, 2H). D369 749.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.95(s, 1H), 10.05-9.61 (m, 2H, TFA salt), 8.15 (s, 1H), 7.56-7.46 (m, 2H),6.90 (d, J = 4.6 Hz, 2H), 6.54-6.45 (m, 2H), 5.05 (dd, J = 13.2, 5.1 Hz,1H), 4.40- 4.28 (m, 2H), 4.27-4.15 (m, 4H), 4.12-3.98 (m, 2H), 3.90 (s,6H), 3.78 (s, 2H), 3.70 (s, 2H), 3.60 (d, J = 2.0 Hz, 3H), 3.52 (s, 3H),3.41 (s, 3H), 3.17 (s, 1H), 2.99-2.90 (m, 3H), 2.68-2.52 (m, 2H),2.47-2.28 (m, 1H), 2.13 (d, J = 13.9 Hz, 2H), 2.00-1.88 (m, 3H). D370749.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.99-9.58 (m, 2H, TFAsalt), 8.63 (s, 1H), 7.92 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.41 (s,2H), 6.54-6.45 (m, 2H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.42- 4.27 (m,2H), 4.25-4.14 (m, 4H), 4.08 (s, 3H), 4.05-3.95 (m, 2H), 3.94 (s, 6H),3.77 (s, 2H), 3.69 (s, 2H), 3.54 (s, 3H), 3.38 (s, 3H), 3.17 (d, J = 6.7Hz, 1H), 2.96 (s, 3H), 2.65-2.51 (m, 2H), 2.43- 2.36 (m, 1H), 2.12 (d, J= 14.3 Hz, 2H), 2.00-1.88 (m, 3H). D371 805.45 1H NMR (400 MHz,Methanol-d4) δ 7.86 (d, J = 9.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.46(s, 1H), 7.06-6.97 (m, 2H), 6.90-6.79 (m, 3H), 5.14 (dd, J = 13.3, 5.1Hz, 1H), 4.55-4.39 (m, 4H), 4.01- 3.86 (m, 6H), 3.74 (s, 3H), 3.69-3.52(m, 3H), 3.41-3.36 (m, 1H), 3.28-3.16 (m, 2H), 3.13-2.98 (m, 4H),2.96-2.86 (m, 2H), 2.85-2.75 (m, 1H), 2.74-2.65 (m, 1H), 2.60-2.43 (m,2H), 2.27 (s, 1H), 2.22-2.15 (m, 1H), 2.14-1.92 (m, 8H), 1.73-1.59 (m,2H).

Example 83—Preparation of Compounds DD1-DD10

In analogy to the procedures described in the examples above, compoundsDD1-DD10 were prepared using the appropriate starting materials.

Compound No. LCMS ¹H NMR DD1 942.5 ¹H NMR (300 MHz, DMSO-d6) δ 9.45 (s,1H), 8.98 (s, 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.60 (t, J = 6.0 Hz, 1H),8.19 (s, 1.0H, FA), 7.87 (s, 1H), 7.56 (d, J = 5.6 Hz, 1H), 7.47-7.35(m, 5H), 6.72 (s, 2H), 4.57 (d, J = 9.5 Hz, 1H), 4.47-4.33 (m, 3H),4.30-4.21 (m, 1H), 3.97 (s, 2H), 3.80 (s, 6H), 3.68-3.50 (m, 18H), 2.58(t, J = 6.1 Hz, 2H), 2.44 (s, 3H), 2.18 (s, 3H), 2.11-2.00 (m, 1H),1.97-1.85 (m, 1H), 0.95 (s, 9H). DD2 754.2 ¹H NMR (400 MHz, DMSO-d6) δ11.12 (s, 1H), 9.43 (s, 1H), 8.71 (d, J = 5.8 Hz, 1H), 8.22 (s, 1, 5H,FA), 8.11 (s, 1H), 7.88-7.81 (m, 2H), 7.54 (d, J = 5.6 Hz, 1H), 7.40 (s,1H), 7.35 (d, J = 8.6 Hz, 1H), 6.72 (s, 2H), 5.16-5.07 (m, 1H), 4.68 (s,2H), 3.80 (s, 6H), 3.62-3.58 (m, 5H), 3.31-3.10 (m, 7H), 2.93-2.83 (m,1H), 2.46 (s, 2H), 2.21 (s, 3H), 2.17 (s, 3H), 2.16-1.94 (m, 2H). DD3740.45 ¹H NMR (300 MHz, Methanol-d4) δ 9.53 (s, 1H), 8.70 (d, J = 5.8Hz, 1H), 8.55 (s, 1H, FA), 7.74 (s, 1H), 7.62 (d, J = 5.7 Hz, 1H), 7.38(t, J = 8.1 Hz, 1H), 6.77 (s, 2H), 6.63 (d, J = 7.8 Hz, 1H), 6.44 (d, J= 8.4 Hz, 1H), 5.21 (dd, J = 10.9, 5.7 Hz, 1H), 4.52-4.25 (m, 2H), 4.12-4.00 (m, 1H), 3.90 (s, 8H), 3.85-3.75 (m, 6H), 3.71 (s, 3H), 3.53- 3.42(m, 2H), 2.93-2.70 (m, 7H), 2.64 (s, 3H), 2.26-2.17 (m, 1H). DD4 709.4¹H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.48 (s, 1H), 8.75 (d, J =5.7 Hz, 2H), 7.92 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.29 (t, J = 7.7Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.87 (s, 2H), 6.74 (d, J = 8.0 Hz,1H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.37-4.26 (m, 2H), 4.22-4.13 (m,2H), 3.89 (s, 7H), 3.62 (s, 3H), 3.21-3.03 (m, 4H), 2.98-2.84 (m, 1H),2.77-2.63 (m, 3H), 2.30-2.23 (m, 1H), 2.10-1.98 (m, 1H), 1.84-1.66 (m,2H), 1.66-1.53 (m, 2H), 1.44-1.29 (m, 8H). DD5 736.45 ¹H NMR (400 MHz,Methanol-d4) δ 9.51 (s, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.56 (s, 1H, FA),7.76 (s, 1H), 7.61 (dd, J = 5.8, 0.9 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H),6.87 (s, 2H), 6.67 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.19(dd, J = 11.0, 5.7 Hz, 1H), 4.29 (s, 2H), 3.96 (s, 6H), 3.68 (s, 3H),3.37-3.36 (m, 1H), 3.14-3.02 (m, 3H), 2.91- 2.70 (m, 6H), 2.63 (s, 3H),2.24-2.17 (m, 1H), 1.87-1.76 (m, 2H), 1.74-1.64 (m, 2H), 1.54-1.36 (m,8H). DD6 722.54 ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.45 (s, 1H),8.72 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 44.8 Hz, 2H), 7.55 (d, J = 5.7Hz, 1H), 6.84 (s, 2H), 5.22-5.02 (m, 0H), 4.98 (s, 1H), 4.71 (s, 1H),4.35 (s, 2H), 3.94-3.78 (m, 6H), 3.59 (s, 3H), 3.13-2.80 (m, 2H), 2.73(s, 2H), 2.67-2.53 (m, 1H), 2.05 (s, 2H). DD7 800.3 1H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 9.40 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H),8.14-8.04 (m, 3H), 7.92 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J =8.8 Hz, 2H), 7.53 (d, J = 5.6 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.74(s, 2H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 4.06 (q, J = 5.2 Hz, 1H), 4.02(t, J = 6.4 Hz, 2H), 3.82 (s, 6H), 3.64 (s, 2H), 3.56 (s, 3H), 3.29-3.12(m, 5H), 3.00 (s, 3H), 2.95-2.82 (m, 1H), 2.64-2.50 (m, 2H), 2.22 (s,3H), 2.06 (d, J = 11.5 Hz, 1H), 1.71 (d, J = 15.0 Hz, 0H), 1.71 (s, 2H),1.59 (q, J = 7.3 Hz, 2H). DD8 814.3 1H NMR (400 MHz, DMSO-d6) δ 11.11(s, 1H), 9.40 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 8.23 (s, 1H), 8.10-8.01(m, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.76-7.64 (m, 3H), 7.52(d, J = 6.2 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.72 (s, 2H), 5.15 (dd, J= 12.9, 5.4 Hz, 1H), 4.00 (t, J = 6.3 Hz, 2H), 3.81 (s, 6H), 3.58 (d, J= 14.7 Hz, 5H), 3.18 (d, J = 6.3 Hz, 1H), 3.15 (s, 5H), 2.94 (s, 2H),2.92-2.82 (m, 1H), 2.62 (s, 1H), 2.59-2.50 (m, 1H), 2.16 (s, 3H), 2.07(d, J = 11.7 Hz, 1H), 1.73 (t, J = 7.0 Hz, 2H), 1.49 (d, J = 5.5 Hz,2H), 1.42 (d, J = 7.9 Hz, 3H). DD9 571.61 ¹H NMR (400 MHz, DMSO-d6) δ8.32 (s, 1H), 8.09-8.02 (m, 1H), 7.82-7.77 (m, 1H), 7.73 (s, 1H), 7.63(s, 0H), 6.87 (d, J = 8.0 Hz, 1H), 6.82 (s, 2H), 5.09 (dt, J = 11.9, 5.8Hz, 1H), 3.92 (d, J = 3.9 Hz, 5H), 3.86 (d, J = 3.7 Hz, 6H), 3.51 (d, J= 2.0 Hz, 4H), 3.15 (s, 1H), 2.08 (d, J = 2.6 Hz, 4H). DD10 803.2 1H NMR(300 MHz, DMSO) δ 11.13 (s, 1H), 8.20 (s, FA, 1H), 8.09 (d, J = 8.3 Hz,1H), 7.90 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.69-7.59 (m,1H), 7.58-7.49 (m, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.34-7.23 (m, 2H),6.73 (s, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 5.05-4.94 (m, 1H), 3.81(s, 6H), 3.73-3.67 (m, 1H), 3.03-2.89 (m, 2H), 2.88-2.81 (m, 1H),2.66-2.53 (m, 2H), 2.49-2.39 (m, 6H), 2.36-2.21 (m, 6H), 2.14-1.99 (m,3H), 1.89-1.75 (m, 2H), 1.72- 1.45 (m, 7H), 1.26-1.06 (m, 2H).

Example 84—Preparation of Compounds D372-D476

In analogy to the procedures described in the examples above, compoundsD372-D476 were prepared using the appropriate starting materials.

Compound No. LCMS ¹H NMR D372 638.25 ¹H NMR (400 MHz, DMSO-d6) δ 11.13(s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 14.1 Hz,2H), 7.57 (d, J = 5.6 Hz, 1H), 7.36-7.28 (m, 2H), 6.79 (s, 2H),5.18-5.01 (m, 2H), 4.25-3.92 (m, 3H), 3.84 (s, 7H), 3.61 (s, 4H),2.96-2.81 (m, 1H), 2.70-2.53 (m, 3H), 2.10-2.01 (m, 1H). D373 691.30 ¹HNMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.45 (d, J = 0.8 Hz, 1H), 8.73(d, J = 5.7 Hz, 1H), 8.18 (s, FA, 1H), 7.89 (s, 1H), 7.67- 7.57 (m, 2H),6.81-6.72 (m, 3H), 6.66 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (dd, J = 12.9,5.4 Hz, 1H), 3.82 (s, 6H), 3.74 (s, 4H), 3.58 (d, J = 20.8 Hz, 6H),2.95-2.82 (m, 1H), 2.63-2.52 (m, 2H), 2.46-2.41 (m, 3H), 2.04-1.97 (m,1H), 1.77-1.70 (m, 4H). D374 677.30 ¹H NMR (400 MHz, MeOD) δ 9.59 (s,1H), 8.71 (d, J = 6.1 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J = 6.0 Hz, 1H),7.67-7.60 (m, 1H), 6.91 (s, 2H), 6.59 (d, J = 7.8 Hz, 2H), 5.11 (dd, J =13.3, 5.1 Hz, 1H), 4.47 (s, 2H), 4.40 (d, J = 7.0 Hz, 2H), 4.00 (s, 6H),3.92 (s, 2H), 3.80 (s, 2H), 3.75 (s, 3H), 3.62-3.55 (m, 3H), 3.31-3.21(m, 1H), 2.98-2.85 (m, 1H), 2.85-2.74 (m, 1H), 2.55-2.39 (m, 1H),2.33-2.24 (m, 2H), 2.21-2.06 (m, 3H). D375 624.25 ¹H NMR (300 MHz,Methanol-d4) δ 9.57 (s, 1H), 8.70 (d, J = 6.0 Hz, 1H), 7.90 (s, 1H),7.77 (dd, J = 14.9, 7.1 Hz, 2H), 7.09 (d, J = 10.5 Hz, 2H), 6.89 (s,2H), 5.41-5.20 (m, 1H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.86-4.60 (m,4H), 4.49 (d, J = 4.5 Hz, 2H), 4.44-4.27 (m, 2H), 3.97 (d, J = 14.5 Hz,6H), 3.73 (s, 3H), 3.01-2.74 (m, 2H), 2.60-2.41 (m, 1H), 2.25-2.13 (m,1H). D376 652.30 ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.81 (s,TFA, 1H), 9.48 (d, J = 0.8 Hz, 1H), 8.75 (d, J = 5.7 Hz, 1H), 7.96-7.89(m, 2H), 7.57 (d, J = 5.7 Hz, 1H), 7.44-7.34 (m, 2H), 6.88 (s, 2H), 5.15(dd, J = 12.8, 5.4 Hz, 2H), 4.74-4.57 (m, 2H), 4.55-4.42 (m, 2H), 4.09(s, 1H), 3.92 (s, 6H), 3.63 (s, 3H), 2.97-2.84 (m, 1H), 2.66- 2.52 (m,2H), 2.10-2.03 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H). D377 677.35 ¹H NMR(400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.16 (s, 1H), 7.73 (s, 1H), 7.41 (d,J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz,1H), 6.74 (d, J = 20.0 Hz, 3H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H),4.38-4.15 (m, 2H), 3.93 (s, 3H), 3.79 (s, 6H), 3.73 (d, J = 12.3 Hz,3H), 3.57-3.52 (m, 5H), 2.97-2.84 (m, 1H), 2.75-2.64 (m, 2H), 2.64-2.55(m, 1H), 2.48-2.38 (m, 4H), 2.38-2.20 (m, 6H), 2.03-1.94 (m, 1H), 1.74(d, J = 12.4 Hz, 2H), 1.52-1.42 (m, 1H), 1.41-1.32 (m, 2H), 1.31-1.17(m, 2H). D378 624.30 ¹H NMR (300 MHz, Methanol-d4) δ 9.56 (s, 1H), 8.69(d, J = 5.9 Hz, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.3 Hz,1H), 7.33-7.16 (m, 2H), 6.89 (s, 2H), 5.40-5.07 (m, 2H), 4.84-4.61 (m,4H), 4.59- 4.44 (m, 2H), 4.44-4.28 (m, 2H), 4.07-3.85 (m, 6H), 3.73 (s,3H), 3.01-2.86 (m, 1H), 2.86-2.75 (m, 1H), 2.61-2.43 (m, 1H), 2.25-2.14(m, 1H). D379 810.35 ¹H NMR (400 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.70(d, J = 5.8 Hz, 1H), 8.56 (s, 1H, FA), 7.78 (s, 1H), 7.69-7.56 (m, 2H),6.88 (s, 2H), 6.65-6.53 (m, 2H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H),4.53-4.24 (m, 4H), 4.06 (d, 2H), 3.98 (s, 6H), 3.76 (d, J = 8.0 Hz, 2H),3.72 (s, 3H), 3.56-3.48 (m, 2H), 3.16-3.01 (m, 2H), 2.99-2.85 (m, 1H),2.84- 2.64 (m, 3H), 2.60-2.40 (m, 3H), 2.36 (s, 2H), 2.21-2.11 (m, 3H),2.05 (d, J = 13.9 Hz, 2H), 1.92 (s, 1H), 1.59-1.38 (m, 2H). D380 661.351H), 9.49 (s, 1H), 8.75 (d, J = 5.9 Hz, 1H), 7.99 (s, 1H), 7.56 (d, J =5.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.12 (t, J = 2.0 Hz, 1H), 7.04(d, J = 2.0 Hz, 2H), 6.74-6.67 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H),4.32 (d, J = 16.6 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.86 (s, 3H), 3.67(s, 6H), 3.61 (s, 3H), 3.39 (s, 2H), 2.98-2.84 (m, 1H), 2.63- 2.59 (m,1H), 2.42-2.33 (m, 1H), 2.02-1.95 (m, 1H), 1.90-1.72 (m, 4H). D381767.40 ¹H NMR (400 MHz, DMSO-d6) δ 10.86-10.81 (m, HCl, 1H), 9.52 (s,1H), 8.80-8.73 (m, 1H), 8.52 (s, 3H), 8.07 (s, 1H), 7.93 (d, J = 8.2 Hz,1H), 7.72 (s, 1H), 7.44-7.34 (m, 2H), 6.88 (d, J = 6.1 Hz, 2H),5.93-5.84 (m, 1H), 5.75-5.67 (m, 1H), 5.53-5.21 (m, 2H), 4.81-4.73 (m,1H), 4.67-4.53 (m, 1H), 4.52-4.44 (m, 2H), 4.33- 4.29 (m, 1H), 4.17-4.12(m, 1H), 3.92 (s, 3H), 3.87 (s, 4H), 3.64 (s, 3H), 3.13-3.05 (m, 1H),2.93-2.84 (m, 1H), 2.70-2.56 (m, 1H), 2.18-2.11 (m, 2H), 0.98-0.90 (m,6H). D382 663.35 ¹H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.47 (s,1H), 8.92 (s, 1H, FA), 8.76 (d, J = 5.7 Hz, 1H), 7.90 (s, 1H), 7.59 (d,J = 5.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.87 (s, 2H), 6.75-6.52 (m,2H), 5.19 (dd, J = 9.1, 6.3 Hz, 1H), 4.49 (d, J = 16.8 Hz, 1H),4.38-4.15 (m, 3H), 3.91 (s, 7H), 3.76 (s, 2H), 3.62 (s, 6H), 3.21-3.04(m, 2H), 3.04-2.79 (m, 2H), 2.21-1.90 (m, 4H). D383 667.30 ¹H NMR (400MHz, DMSO-d6 with a drop of D₂O) δ 9.46 (s, 1H), 8.75 (d, J = 5.7 Hz,1H), 7.88 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 5.6 Hz, 1H),6.86 (s, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.67 (dd, J = 8.4, 2.1 Hz, 1H),5.21 (dd, J = 9.6, 5.6 Hz, 1H), 4.29 (s, 2H), 3.91 (d, J = 8.4 Hz, 8H),3.81 (s, 2H), 3.61 (s, 3H), 3.38 (d, J = 12.6 Hz, 2H), 3.13 (t, J = 12.0Hz, 2H), 3.05-2.95 (m, 1H), 2.82 (dd, J = 17.9, 5.5 Hz, 1H), 2.15 (d, J= 14.1 Hz, 2H), 2.01 (t, J = 12.8 Hz, 2H). D384 753.40 ¹H NMR (400 MHz,DMSO-d6) δ 10.71 (s, 1H, HCl salt), 9.49 (s, 1H), 8.79-8.72 (m, 1H),8.51 (br s, 3H), 7.99 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.67-7.59 (m,1H), 7.39-7.01 (m, 3H), 6.87 (d, J = 5.1 Hz, 2H), 5.86-5.78 (m, 1H),5.76-5.68 (m, 1H), 5.35-5.02 (m, 2H), 4.80-4.67 (m, 1H), 4.60-4.54 (m,1H), 4.52-4.41 (m, 3H), 4.34-4.22 (m, 2H), 4.16-4.10 (m, 1H), 3.94-3.82(m, 7H), 3.63 (s, 3H), 3.20-3.06 (m, 1H), 2.91-2.82 (m, 1H), 2.46-2.36(m, 1H), 2.21-2.06 (m, 2H), 0.97-0.90 (m, 6H). D385 636.35 ¹H NMR (300MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H),8.13 (s, 0.1H, FA salt), 7.90-7.81 (m, 2H), 7.51 (d, J = 5.7 Hz, 1H),7.37-7.27 (m, 2H), 6.94 (s, 2H), 5.18-4.99 (m, 2H), 3.84 (s, 6H), 3.60(s, 4H), 3.28-3.25 (m, 2H), 2.99-2.72 (m, 3H), 2.61-2.53 (m, 2H),2.11-1.99 (m, 1H), 1.21 (t, J = 7.5 Hz, 3H). D386 650.30 ¹H NMR (300MHz, DMSO-d6) δ 11.12 (s, 1H), 9.45 (s, 1H), 8.73 (dd, J = 5.7, 2.3 Hz,1H), 8.13 (s, 0.1H, FA salt), 7.89-7.80 (m, 2H), 7.49 (dd, J = 6.0, 2.1Hz, 1H), 7.37-7.28 (m, 2H), 6.92 (s, 2H), 5.12 (dd, J = 12.9, 5.3 Hz,1H), 4.63 (s, 1H), 3.90-3.68 (m, 6H), 3.60 (s, 4H), 3.44-3.37 (m, 1H),2.99-2.72 (m, 3H), 2.62-2.52 (m, 2H), 2.11-1.95 (m, 1H), 1.29-1.12 (m,6H). D387 647.25 ¹H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.45 (s,1H), 8.73 (d, J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.48-7.36 (m, 2H),7.01-6.89 (m, 3H), 6.73-6.65 (m, 2H), 5.11-5.04 (m, 1H), 4.31-4.18 (m,2H), 3.82 (s, 3H), 3.60 (s, 7H), 3.52 (s, 2H), 2.94-2.87 (m, 1H), 2.67-2.61 (m, 1H), 2.46-2.34 (m, 4H), 2.04-1.92 (m, 2H), 1.83-1.73 (m, 4H).D388 705.45 ¹H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.48 (s, 1H),9.07 (br s, 1H), 8.76 (d, J = 5.7 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J =8.2 Hz, 1H), 7.61 (d, J = 5.8 Hz, 1H), 6.88 (s, 2H), 6.78 (d, J = 2.1Hz, 1H), 6.67 (dd, J = 8.3, 2.2 Hz, 1H), 5.14 (dd, 1H), 4.38-4.24 (m,2H), 3.97-3.88 (m, 8H), 3.83 (s, 2H), 3.63 (s, 3H), 3.46-3.35 (m, 3H),3.18-3.06 (m, 3H), 2.76-2.66 (m, 1H), 2.22-2.13 (m, 2H), 2.11- 1.80 (m,5H). D389 663.30 ¹H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.74 (d, J =5.7 Hz, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.36(d, J = 8.7 Hz, 1H), 6.80 (s, 2H), 6.70-6.64 (m, 2H), 4.64 (dd, J =10.8, 6.8 Hz, 1H), 4.38-4.25 (m, 1H), 4.21-4.07 (m, 1H), 3.96-3.80 (m,8H), 3.66-3.59 (m, 7H), 3.23-3.11 (m, 3H), 2.94-2.74 (m, 3H), 2.09-1.80(m, 8H). D390 663.50 ¹H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.99 (s,1H, TFA), 8.76 (d, J = 5.7 Hz, 1H), 7.91 (s, 1H), 7.60 (d, J = 5.7 Hz,1H), 7.54 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.88 (s, 2H),6.73-6.64 (m, 2H), 4.41-4.27 (m, 5H), 3.92 (s, 6H), 3.76 (s, 3H), 3.64(s, 4H), 3.45-3.34 (m, 2H), 3.34-3.06 (m, 4H), 2.44-2.29 (m, 2H), 2.19-1.85 (m, 6H). D391 667.45 ¹H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H),9.54 (s, 1H), 9.10 (s, 1H), 8.97 (d, J = 8.2 Hz, 1H), 8.82 (d, J = 5.7Hz, 1H), 8.37 (d, J = 5.9 Hz, 1H), 7.96 (s, 1H), 7.65 (d, J = 5.7 Hz,1H), 6.94 (s, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.85-4.71 (m, 1H),4.42-4.32 (m, 2H), 4.12-3.89 (m, 11H), 3.69 (s, 3H), 3.27-3.15 (m, 3H),2.98-2.78 (m, 1H), 2.71- 2.60 (m, 1H), 2.32-1.99 (m, 6H). D392 665.25 ¹HNMR (300 MHz, Methanol-d4) δ 9.63 (s, 1H), 8.72 (d, J = 6.4 Hz, 1H),8.08 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.23(dt, J = 7.9, 1.2 Hz, 1H), 7.02 (t, J = 2.0 Hz, 1H), 6.91 (s, 2H), 6.71(ddd, J = 8.0, 2.5, 1.1 Hz, 1H), 4.86-4.85 (m, 1H), 4.46 (s, 2H), 4.00(s, 6H), 3.85 (s, 2H), 3.75 (d, J = 9.0 Hz, 5H), 3.58 (d, J = 12.9 Hz,2H), 3.25 (t, J = 11.8 Hz, 2H), 2.95-2.65 (m, 2H), 2.34- 2.05 (m, 6H).D393 571.25 ¹H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.45 (d, J = 0.8Hz, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.19 (.1.0 FA, s, 1H), 7.89 (s, 1H),7.63- 7.50 (m, 2H), 7.36 (s, 1H), 6.74 (s, 2H), 5.27 (dd, J = 11.5, 5.1Hz, 1H), 3.83 (s, 6H), 3.60 (d, J = 4.2 Hz, 5H), 2.92 (d, J = 11.3 Hz,2H), 2.84-2.68 (m, 1H), 2.68-2.53 (m, 1H), 2.49-2.35 (m, 2H), 2.24- 2.09(m, 3H), 1.80 (d, J = 12.8 Hz, 2H), 1.58-1.38 (m, 2H). D394 613.25 ¹HNMR (300 MHz, Methanol-d4) δ 9.60 (s, 1H), 8.71 (d, 1H), 7.97 (s, 1H),7.85 (d, 1H), 6.91 (s, 2H), 6.70 (s, 1H), 6.12 (dd, 1H), 4.48 (s, 2H),4.00 (s, 6H), 3.75 (s, 4H), 3.71 (s, 1H), 3.58-3.42 (m, 1H), 3.27 (s,1H), 3.06-2.95 (m, 1H), 2.90-2.76 (m, 2H), 2.60 (d, 3H), 2.40-2.27 (m,2H), 2.12 (dd, 4H). D395 667.45 ¹H NMR (300 MHz, DMSO-d6) δ 10.87 (s,1H), 9.45 (s, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.73 (d, J = 5.6 Hz, 1H),8.54 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H, FA), 7.88 (s, 1H), 7.63-7.55 (m,1H), 6.89 (d, J = 1.2 Hz, 1H), 6.74 (s, 2H), 4.76 (ddd, J = 12.9, 8.4,5.3 Hz, 1H), 3.82 (d, J = 4.1 Hz, 10H), 3.61 (s, 3H), 3.58 (s, 2H),2.84-2.74 (m, 1H), 2.55 (s, 2H), 2.48-2.40 (m, 3H), 2.25-2.13 (m, 1H),2.05-1.93 (m, 1H), 1.75 (s, 4H). D396 640.31 ¹H NMR (400 MHz, DMSO-d6) δ10.97 (s, 1H), 8.19 (s, FA, 1H), 7.41-7.26 (m, 2H), 6.72-6.66 (m, 2H),6.53 (s, 2H), 5.09 (dd, J = 13.2, 5.0 Hz, 1H), 4.31 (d, J = 16.6 Hz,1H), 4.18 (d, J = 16.6 Hz, 1H), 3.79 (s, 6H), 3.77 (d, J = 7.1 Hz, 2H),3.74-3.66 (m, 4H), 3.54 (s, 3H), 2.97-2.84 (m, 1H), 2.77 (s, 2H),2.64-2.59 (m, 2H), 2.40- 2.28 (m, 5H), 2.04 (s, 3H), 2.01-1.95 (m, 3H).D397 751.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.19 (br s, TFAsalt, 2H), 7.45-7.38 (m, 1H), 7.28 (s, 1H), 6.74-6.66 (m, 4H), 5.07 (dd,J = 13.3, 5.1 Hz, 1H), 4.37-4.16 (m, 4H), 3.87 (s, 6H), 3.74 (d, J = 8.5Hz, 2H), 3.67 (d, J = 6.9 Hz, 2H), 3.65 (s, 5H), 3.53-3.50 (m, 2H), 3.21(s, 1H), 3.07-2.85 (m, 6H), 2.65-2.55 (m, 1H), 2.43- 2.31 (m, 4H),2.20-2.07 (m, 3H), 2.05 (s, 3H), 2.02-1.87 (m, 5H), 1.58-1.39 (m, 2H).D398 761.2 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H, FA), 8.15 (d, J =2.5 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.22(dd, J = 8.7, 2.3 Hz, 1H), 7.14-6.71 (m, 3H), 5.06 (dd, J = 12.8, 5.3Hz, 1H), 4.03 (d, J = 13.0 Hz, 2H), 3.85 (s, 6H), 3.59 (s, 3H), 3.54 (s,2H), 3.00-2.80 (m, 3H), 2.65-2.52 (m, 2H), 2.48-2.24 (m, 10H), 2.06-1.96(m, 1H), 1.73 (d, J = 12.6 Hz, 2H), 1.60-1.54 (m, 1H), 1.37 (t, J = 7.3Hz, 2H), 1.16 (q, J = 11.6 Hz, 2H). D399 747.3 ¹H NMR (300 MHz, DMSO-d6)δ 10.99 (s, 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H, FA), 8.15 (d, J= 2.6 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.6, 2.3 Hz, 1H),7.14 (d, J = 2.3 Hz, 1H), 7.12- 6.72 (m, 3H), 5.10 (dd, J = 13.2, 5.1Hz, 1H), 4.33 (d, J = 16.7 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H), 3.85 (s,6H), 3.72 (d, J = 12.1 Hz, 2H), 3.59 (s, 3H), 3.53 (s, 2H), 3.01-2.82(m, 1H), 2.78-2.51 (m, 4H), 2.46-2.20 (m, 10H), 1.98 (d, J = 13.3 Hz,1H), 1.73 (d, J = 12.4 Hz, 2H), 1.47-1.36 (m, 3H), 1.24 (q, J = 11.2 Hz,2H). D400 751.5 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.63 (s, 1H),7.91 (s, 1H), 7.47-7.39 (m, 3H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.20(d, J = 2.3 Hz, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.40-4.14 (m, 4H),4.08 (s, 3H), 3.92 (s, 6H), 3.78-3.74 (m, 8H), 3.54 (s, 3H), 3.14 (s,4H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.75 (t, J = 11.8 Hz, 2H),2.65-2.56 (m, 1H), 2.43-2.34 (m, 1H), 2.04-1.95 (m, 1H), 1.78 (d, J =12.4 Hz, 2H), 1.64-1.46 (m, 3H), 1.38-1.23 (m, 2H). D401 690.3 ¹H NMR(300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.15 (s,1H, FA), 7.41-7.32 (m, 1H), 7.20-6.73 (m, 3H), 6.68 (dd, J = 5.1, 2.5Hz, 2H), 5.09 (dd, J = 13.3, 5.0 Hz, 1H), 4.45-4.10 (m, 2H), 4.00 (t, J= 7.5 Hz, 2H), 3.87 (s, 6H), 3.81-3.66 (m, 6H), 2.94-2.83 (m, 1H), 2.75(s, 2H), 2.64-2.52 (m, 2H), 2.42-2.25 (m, 2H), 1.98 (t, J = 7.0 Hz, 3H),1.75 (q, J = 7.5 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). D402 749.35 ¹H NMR(400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.95-9.63 (m, 2H, TFA salt), 8.63(s, 1H), 7.92 (s, 1H), 7.45-7.38 (m, 3H), 6.73-6.66 (m, 2H), 5.07 (dd, J= 13.3, 5.1 Hz, 1H), 4.43-4.28 (m, 3H), 4.24- 4.15 (m, 3H), 4.08 (s,3H), 4.03-3.98 (m, 2H), 3.94 (s, 6H), 3.76- 3.62 (m, 4H), 3.54 (s, 3H),3.22-3.12 (m, 2H), 2.97-2.88 (m, 4H), 2.70-2.56 (m, 2H), 2.44-2.30 (m,2H), 2.12 (d, J = 14.1 Hz, 2H), 2.02-1.89 (m, 3H). D403 662.15 ¹H NMR(400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.41 (s, J = 2.6 Hz, 1H), 8.16 (s,1H, FA), 7.37 (d, J = 8.8 Hz, 1H), 6.86-7.08 (m, 3H), 6.72-6.65 (m, 2H),5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J =16.6 Hz, 1H), 3.87 (s, 6H), 3.79-3.67 (m, 6H), 3.60 (s, 3H), 2.97-2.84(m, 2H), 2.76 (s, 2H), 2.63-2.55 (m, 3H), 2.31-2.42 (m, 2H), 2.02-1.94(m, 3H). D404 688.15 ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.34 (d,J = 2.6 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H, FA), 7.37 (d, J = 8.8 Hz,1H), 7.16- 6.73 (m, 3H), 6.68 (dq, J = 4.0, 2.3 Hz, 2H), 6.03 (ddd, J =17.2, 10.5, 5.3 Hz, 1H), 5.33-5.00 (m, 3H), 4.68 (d, J = 5.5 Hz, 2H),4.31 (d, J = 16.7 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 3.90-3.79 (m, 7H),3.77-3.71 (m, 2H), 3.72-3.63 (m, 3H), 3.00-2.82 (m, 1H), 2.76 (s, 2H),2.59 (d, J = 17.1 Hz, 3H), 2.43-2.28 (m, 1H), 1.98 (t, J = 6.9 Hz, 3H).D405 777.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.61 (s, 1H),8.19- 8.14 (m, 1H, FA), 7.89-7.82 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H),7.36- 7.29 (m, 2H), 6.72-6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H),4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 4.08 (s, 3H), 3.87(s, 6H), 3.79 (s, 2H), 3.58 (s, 4H), 3.53 (s, 3H), 3.08-3.01 (m, 2H),2.98-2.84 (m, 1H), 2.68-2.55 (m, 2H), 2.43-2.30 (m, 6H), 2.11 (d, J =7.0 Hz, 2H), 2.02-1.93 (m, 1H), 1.77-1.67 (m, 6H), 1.59 (s, 1H),1.21-1.17 (m, 2H). D406 676.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H),8.41 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H, FA), 8.15 (d, J = 2.5 Hz, 1H),7.63 (d, J = 8.3 Hz, 1H), 7.15-6.74 (m, 4H), 6.64 (dd, J = 8.3, 2.1 Hz,1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 3.99-3.85 (m, 4H), 3.87 (s, 6H),3.70 (s, 2H), 3.59 (s, 3H), 2.97-2.80 (m, 1H), 2.77 (s, 2H), 2.63-2.53(m, 4H), 2.02 (t, J = 7.0 Hz, 3H). D407 773.89 ¹H NMR (400 MHz, DMSO-d6)δ 10.98 (s, 1H), 9.42 (s, 1H, TFA), 9.25 (s, 1H, TFA), 8.50 (d, J = 2.7Hz, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.44-7.38 (m, 1H), 7.11-6.79 (m, 3H),6.70 (dd, J = 5.8, 2.4 Hz, 2H), 5.07 (dd, J = 13.3, 5.1 Hz, 1H),4.38-4.14 (m, 4H), 3.95 (s, 6H), 3.66 (d, J = 7.8 Hz, 2H), 3.61 (s, 3H),3.54-3.39 (m, 4H), 3.21- 3.14 (m, 1H), 3.02-2.82 (m, 7H), 2.64-2.56 (m,1H), 2.43-2.35 (m, 1H), 2.15-2.07 (m, 3H), 2.02-1.88 (m, 5H), 1.48 (q, J= 12.8 Hz, 2H), 1.26 (q, J = 7.2, 6.7 Hz, 1H). D408 662.3 ¹H NMR (300MHz, DMSO-d6) δ 10.95 (s, 1H), 8.41 (d, J = 2.6 Hz, 1H), 8.21 (s, 1H,FA), 8.17-8.10 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.18-6.73 (m, 3H),6.54-6.42 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.9Hz, 1H), 4.16 (d, J = 16.9 Hz, 1H), 3.87 (s, 6H), 3.79 (q, J = 7.9 Hz,4H), 3.70 (s, 2H), 3.59 (s, 3H), 2.99-2.81 (m, 1H), 2.80-2.74 (m, 2H),2.63-2.52 (m, 2H), 2.41-2.29 (m, 2H), 2.05-1.89 (m, 3H). D409 676.25 ¹HNMR (300 MHz, Methanol-d4) δ 8.55 (s, 1H, FA), 7.68 (s, 1H), 7.42 (d, J= 8.2 Hz, 1H), 7.03-6.77 (m, 3H), 6.71 (s, 2H), 5.14 (dd, J = 13.3, 5.1Hz, 1H), 4.48-4.33 (m, 4H), 4.03-3.89 (m, 10H), 3.71 (s, 3H), 3.64-3.54(m, 2H), 3.47-3.37 (m, 2H), 3.00-2.85 (m, 1H), 2.85-2.74 (m, 1H),2.58-2.41 (m, 6H), 2.23-2.13 (m, 1H). D410 787.25 ¹H NMR (300 MHz,DMSO-d6) δ 10.98 (s, 1H), 8.17 (s, 1H, FA), 7.61 (s, 1H), 7.37 (d, J =8.1 Hz, 1H), 6.91 (t, J = 55.2 Hz, 1H), 6.74- 6.65 (m, 2H), 6.61 (s,2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (d, J = 16.6 Hz, 1H), 4.18(d, J = 16.6 Hz, 1H), 3.81 (s, 6H), 3.69 (s, 2H), 3.63-3.58 (m, 6H),3.01-2.88 (m, 4H), 2.65-2.59 (m, 1H), 2.41 (s, 4H), 2.37-2.26 (m, 6H),2.11 (d, J = 6.9 Hz, 2H), 2.02- 1.95 (m, 1H), 1.79-1.64 (m, 6H), 1.54(s, 1H), 1.21-1.08 (m, 2H). D411 680.35 ¹H NMR (400 MHz, DMSO-d6) δ10.96 (s, 1H), 9.06 (s, 1H, TFA salt), 8.15 (s, 1H), 7.56-7.48 (m, 2H),6.91 (s, 2H), 6.55-6.46 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H),4.37-4.25 (m, 3H), 4.19 (d, J = 16.9 Hz, 1H), 3.92 (s, 6H), 3.81 (s,2H), 3.70 (s, 2H), 3.63 (s, 3H), 3.52 (s, 3H), 3.13 (q, J = 11.1 Hz,2H), 2.91 (ddd, J = 17.1, 13.6, 5.3 Hz, 1H), 2.64-2.55 (m, 3H),2.44-2.28 (m, 1H), 2.14 (d, J = 13.9 Hz, 2H), 2.05-1.92 (m, 3H). 19F NMR(377 MHz, DMSO-d6) δ-73.65. D412 680.35 ¹H NMR (400 MHz, DMSO-d6) δ10.95 (s, 1H), 8.90 (s, 1H, TFA salt), 8.63 (s, 1H), 7.93 (s, 1H), 7.52(d, J = 8.3 Hz, 1H), 7.43 (s, 2H), 6.55-6.46 (m, 2H), 5.05 (dd, J =13.3, 5.1 Hz, 1H), 4.36-4.15 (m, 4H), 4.09 (s, 3H), 3.95 (s, 6H), 3.80(s, 2H), 3.69 (s, 2H), 3.55 (s, 3H), 3.14-3.07 (m, 2H), 2.97-2.84 (m,1H), 2.71-2.57 (m, 3H), 2.39-2.31 (m, 1H), 2.17-2.09 (m, 2H), 2.04-1.93(m, 3H). 19F NMR (377 MHz, DMSO-d6) δ-73.66. D413 694.45 ¹H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 8.19-8.14 (m, 1H, FA), 8.12 (s, 1H), 7.64(d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 6.81-6.74 (m, 3H), 6.69-6.62 (m, 1H),5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.82 (s, 6H), 3.74 (s, 4H), 3.61-3.54(m, 5H), 3.51 (s, 3H), 2.95-2.82 (m, 1H), 2.63-2.52 (m, 2H), 2.46-2.39(m, 4H), 2.06-1.97 (m, 1H), 1.78-1.69 (m, 4H). D414 680.4 ¹H NMR (400MHz, DMSO-d6) δ 10.96 (s, 1H), 8.16 (s, 1H, FA), 8.12 (s, 1H), 7.51 (s,1H), 7.37 (d, J = 8.0 Hz, 1H), 6.76 (s, 2H), 6.72- 6.65 (m, 2H), 5.08(dd, J = 13.3, 5.2 Hz, 1H), 4.36-4.12 (m, 2H), 3.82 (s, 6H), 3.61-3.55(m, 9H), 3.51 (s, 3H), 2.94-2.85 (m, 1H), 2.66-2.54 (m, 2H), 2.46-2.40(m, 4H), 2.02-1.95 (m, 1H), 1.76- 1.69 (m, 4H). D415 694.3 ¹H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H, FA), 7.80 (s,1H), 7.62 (d, J = 8.3 Hz, 1H), 7.27 (s, 2H), 6.78 (d, J = 2.1 Hz, 1H),6.68-6.61 (m, 1H), 5.05 (dd, J = 12.9, 5.3 Hz, 1H), 4.08 (s, 3H), 3.84(s, 6H), 3.73 (s, 4H), 3.56 (s, 2H), 3.53 (s, 3H), 2.91-2.81 (m, 1H),2.62-2.52 (m, 2H), 2.46-2.41 (m, 4H), 2.04- 1.96 (m, 1H), 1.77-1.70 (m,4H). D416 680.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.59 (s, 1H),8.18 (s, 1H, FA), 7.80 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.27 (s, 2H),6.72- 6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.35-4.13 (m, 2H),4.08 (s, 3H), 3.85 (s, 6H), 3.59-3.50 (m, 9H), 2.96-2.84 (m, 1H),2.64-2.53 (m, 2H), 2.48-2.36 (m, 4H), 2.02-1.94 (m, 1H), 1.76- 1.69 (m,4H). D417 694.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.65 (s,1H), 8.20 (s, 1H FA), 7.83 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.32 (s,2H), 6.72- 6.64 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (q, J =7.3 Hz, 2H), 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.7 Hz, 1H), 3.85(s, 6H), 3.57 (d, J = 4.1 Hz, 6H), 3.53 (s, 3H), 2.98-2.84 (m, 1H),2.70- 2.52 (m, 2H), 2.49-2.42 (m, 3H), 2.37 (dd, J = 13.2, 4.6 Hz, 1H),2.03-1.94 (m, 1H), 1.74 (t, J = 5.5 Hz, 4H), 1.50 (t, J = 7.3 Hz, 3H).D418 693.45 ¹H NMR (400 MHz, DMSO-d6) δ 11.85 (d, J = 2.7 Hz, 1H), 11.09(s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.17-7.10 (m, 2H), 6.78 (d, J = 2.1Hz, 1H), 6.70 (s, 2H), 6.65 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (dd, J =12.9, 5.4 Hz, 1H), 3.82 (d, J = 22.7 Hz, 12H), 3.55 (s, 3H), 2.95- 2.83(m, 2H), 2.82-2.66 (m, 2H), 2.64-2.53 (m, 4H), 2.01 (dd, J = 9.4, 4.3Hz, 1H), 1.87 (s, 6H). D419 665.25 ¹H NMR (300 MHz, DMSO-d6) δ 12.17 (s,1H), 10.98 (s, 1H), 8.15 (s, 1H, FA), 7.48 (s, 1H), 7.38-7.36 (m, 2H),6.85 (s, 2H), 6.71- 6.68 (m, 2H), 6.58-6.55 (m, 1H), 5.11-5.05 (m, 1H),4.34-4.15 (m, 2H), 3.85 (s, 6H), 3.60 (s, 3H), 3.58 (s, 6H), 2.97-2.89(m, 1H), 2.74-2.72 (m, 3H), 2.40-2.34 (m, 2H), 2.00-1.97 (m, 1H), 1.73(s, 4H), 1.35-1.24 (m, 1H). D420 666.35 ¹H NMR (400 MHz, DMSO-d6) δ13.50 (s, 1H), 10.97 (s, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 7.38 (d, J =8.0 Hz, 1H), 6.88 (s, 2H), 6.73- 6.65 (m, 2H), 5.08 (dd, J = 13.3, 5.1Hz, 1H), 4.31 (d, J = 16.6 Hz, 1H), 4.18 (d, J = 16.5 Hz, 1H), 3.89 (s,6H), 3.69 (s, 2H), 3.60 (s, 4H), 3.55 (s, 3H), 2.96-2.84 (m, 1H),2.64-2.55 (m, 4H), 2.42- 2.22 (m, 2H), 1.98 (d, J = 12.9 Hz, 1H), 1.79(s, 4H). D421 680.45 ¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.45 (s,1H), 8.18 (s, 1H, FA), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.83 (s,2H), 6.72- 6.64 (m, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.31 (d, J =16.6 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 4.12 (s, 3H), 3.87 (s, 6H),3.57 (s, 3H), 3.56-3.53 (m, 6H), 2.95-2.86 (m, 1H), 2.63-2.56 (m, 1H),2.49-2.34 (m, 5H), 2.04-1.94 (m, 1H), 1.79-1.62 (m, 4H). D422 679.25 ¹HNMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.99 (s, 1H), 9.05- 8.75 (m,1H, TFA), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.94 (s, 2H), 6.71 (d,J = 5.7 Hz, 2H), 6.30 (s, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H),4.36-4.15 (m, 4H), 3.95 (s, 6H), 3.76 (s, 2H), 3.65-3.63 (m, 2H),3.62-3.60 (m, 3H), 3.38-3.33 (m, 2H), 3.18-3.05 (m, 2H), 3.00-2.84 (m,1H), 2.67-2.59 (m, 1H), 2.44-2.39 (m, 1H), 2.36 (s, 3H), 2.13 (d, J =13.3 Hz, 2H), 2.01 (d, J = 11.3 Hz, 3H). D423 614.35 ¹H NMR (400 MHz,DMSO-d6) δ 7.53 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.05 (d,J = 8.3 Hz, 2H), 6.56 (s, 2H), 5.00 (dd, J = 13.3, 5.1 Hz, 1H),4.39-4.15 (m, 2H), 3.77 (d, J = 18.2 Hz, 8H), 3.53 (s, 3H), 3.32 (t, J =4.8 Hz, 4H), 2.94-2.81 (m, 1H), 2.79- 2.67 (m, 4H), 2.65-2.55 (m, 1H),2.43-2.28 (m, 4H), 2.03 (s, 3H), 2.01-1.92 (m, 1H). D424 671.4 ¹H NMR(300 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.24 (s, 1H, FA), 7.77 (s, 1H), 7.43(d, J = 8.4 Hz, 1H), 7.25 (s, 2H), 7.21 (d, J = 6.0 Hz, 1H), 7.15 (d,1H), 5.05 (dd, J = 13.2, 5.0 Hz, 1H), 4.34-4.20 (m, 2H), 4.07 (s, 3H),4.00 (d, J = 12.7 Hz, 1H), 3.86 (s, 6H), 3.83-3.77 (m, 1H), 3.28-3.14(m, 4H), 3.06-2.96 (m, 2H), 2.91-2.79 (m, 1H), 2.66-2.55 (m, 1H),2.43-2.20 (m, 1H), 2.00 (s, 1H), 1.26 (d, J = 6.1 Hz, 6H). D425 676.35¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.41 (d, J = 2.6 Hz, 1H),8.19 (d, J = 6.8 Hz, 1H), 8.16 (d, J = 2.6 Hz, 1H, FA), 7.36 (d, J = 8.0Hz, 1H), 6.90 (d, J = 33.7 Hz, 3H), 6.72-6.64 (m, 2H), 5.13- 5.04 (m,1H), 4.31 (d, J = 16.5 Hz, 1H), 4.18 (d, J = 16.6 Hz, 1H), 3.87 (s, 6H),3.60 (s, 3H), 3.54 (d, J = 15.6 Hz, 7H), 2.97-2.84 (m, 1H), 2.63-2.54(m, 1H), 2.45-2.31 (m, 4H), 1.98 (d, J = 12.6 Hz, 1H), 1.71 (s, 4H).D426 679.5 ¹H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.98 (s, 1H),8.24 FA (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20-7.06 (m, 2H), 6.76-6.54(m, 4H), 5.09 (dd, J = 13.3, 5.0 Hz, 1H), 4.40-4.10 (m, 2H), 3.80 (s,6H), 3.60-3.54 (m, 9H), 3.00-2.83 (m, 2H), 2.62 (s, 1H), 2.40 (s, 3H),1.99 (s, 2H), 1.85 (s, 3H), 1.78-1.64 (m, 4H). D427 614.35 ¹H NMR (400MHz, DMSO-d6) δ 10.97 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.31 (d, J =1.2 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H),6.59-6.52 (m, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.16 (m, 2H),3.81 (s, 6H), 3.62 (s, 2H), 3.54 (s, 3H), 3.22- 3.11 (m, 4H), 2.98-2.84(m, 1H), 2.72-2.56 (m, 5H), 2.46-2.36 (m, 1H), 2.33 (s, 3H), 2.04 (s,3H), 2.02-1.94 (m, 1H). D428 666.35 ¹H NMR (300 MHz, DMSO-d6) δ 10.97(s, 1H), 8.36 (s, 1H), 8.15 (d, J = 0.9 Hz, 1H, FA), 7.89 (s, 1H), 7.37(d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 6.93 (s, 2H), 6.69 (d, J = 7.7 Hz,2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.43-4.14 (m, 2H), 3.86 (s, 6H),3.64-3.57 (m, 6H), 3.44 (s, 5H), 2.99-2.84 (m, 2H), 2.68-2.60 (m, 1H),2.45-2.32 (m, 2H), 2.05-1.91 (m, 1H), 1.81-1.68 (m, 4H). D429 627.35 ¹HNMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.14(d, J = 1.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.18 (s, 2H), 6.68 (d, J= 7.7 Hz, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.42-4.14 (m, 2H), 3.88(s, 6H), 3.77 (s, 2H), 3.60 (s, 4H), 3.56 (s, 4H), 2.97- 2.84 (m, 1H),2.69 (s, 3H), 2.64-2.55 (m, 2H), 2.39 (td, J = 13.1, 4.4 Hz, 1H),2.02-1.93 (m, 1H), 1.82 (s, 4H). D430 654.3 ¹H NMR (300 MHz, DMSO-d6) δ11.09 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 6.82 (d, J = 2.1Hz, 1H), 6.73-6.54 (m, 3H), 5.06 (dd, J = 12.8, 5.3 Hz, 1H), 4.14-3.94(m, 5H), 3.85 (s, 6H), 3.49- 3.46 (m, 5H), 3.14-2.97 (m, 2H), 2.96-2.70(m, 2H), 2.68-2.58 (m, 1H), 2.36-2.17 (m, 2H), 2.14-1.95 (m, 7H). D431665.35 ¹H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.94 (s, 1H, TFA),7.50 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 4.0 Hz,1H), 6.92 (s, 2H), 6.87 (dd, J = 10.2, 5.1 Hz, 2H), 6.75-6.66 (m, 2H),5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.12 (m, 4H), 3.95 (s, 6H), 3.76(s, 2H), 3.70 (s, 2H), 3.43-3.31 (m, 5H), 3.17-3.11 (m, 2H), 3.00-2.82(m, 1H), 2.63 (s, 1H), 2.44-2.30 (m, 1H), 2.19- 2.08 (m, 2H), 2.06-1.96(m, 3H). D432 664.3 ¹H NMR (300 MHz, Methanol-d4) δ 8.30 (d, J = 2.6 Hz,1H), 8.20- 8.13 (m, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.10-6.61 (m, 3H),6.26 (dd, J = 7.6, 2.0 Hz, 1H), 5.67 (d, J = 1.8 Hz, 1H), 5.25 (dd, J =12.5, 5.3 Hz, 1H), 4.43 (s, 2H), 4.17-3.96 (m, 10H), 3.72 (s, 3H), 3.67(s, 2H), 3.51-3.45 (m, 2H), 2.99-2.76 (m, 2H), 2.73-2.49 (m, 1H),2.52-2.46 (m, 2H), 2.36-2.23 (m, 1H). D433 666.25 ¹H NMR (300 MHz,DMSO-d6) δ 14.27 (s, 1H), 10.98 (s, 1H), 8.24 (s, 1H, FA), 8.15 (s, 1H),7.61 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.90 (s, 2H), 6.74-6.64 (m, 2H),5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.25 (dd, 2H), 3.90 (s, 6H), 3.74 (s,2H), 3.61 (d, J = 6.9 Hz, 7H), 2.98- 2.84 (m, 1H), 2.79-2.54 (m, 5H),2.42-2.32 (m, 1H), 2.03-1.93 (m, 1H), 1.81 (s, 4H). D434 666.25 ¹H NMR(300 MHz, MeOD) δ 8.85-8.49 (m, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.42 (d,J = 8.2 Hz, 1H), 7.17-7.09 (m, 2H), 6.89 (d, J = 2.2 Hz, 1H), 6.81 (dd,J = 8.2, 2.3 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.49-4.31 (m,4H), 4.04 (s, 6H), 3.85 (s, 2H), 3.78 (s, 3H), 3.73 (s, 2H), 3.56 (d, J= 12.7 Hz, 2H), 3.24 (t, J = 11.9, 11.9 Hz, 2H), 3.02-2.86 (m, 1H),2.85-2.72 (m, 1H), 2.59-2.41 (m, 1H), 2.34-2.22 (m, 2H), 2.21-2.04 (m,3H). D435 665.35 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.23 (s, 1H,FA), 7.61 (d, J = 3.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.05 (d, J =7.7 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.77(s, 2H), 6.70-6.67 (m, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.34-4.14(m, 2H), 3.85 (s, 6H), 3.56 (s, 3H), 3.51-3.50 (m, 6H), 2.98-2.83 (m,1H), 2.68-2.57 (m, 1H), 2.48-2.22 (m, 5H), 2.06-1.91 (m, 1H), 1.72-1.70(m, 4H). D436 614.3 ¹H NMR (300 MHz, Methanol-d4) δ 7.71 (d, J = 8.5 Hz,1H), 7.60 (s, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.6, 2.3 Hz,1H), 6.65 (s, 2H), 6.52 (s, 1H), 5.09 (dd, J = 12.3, 5.4 Hz, 1H), 3.91(d, 8H), 3.58 (d, J = 18.3 Hz, 7H), 2.99-2.89 (m, 4H), 2.87-2.66 (m,3H), 2.21 (s, 3H), 2.18-2.07 (m, 1H). D437 693.4 ¹H NMR (300 MHz,Methanol-d4) 7.41 (d, J = 8.2 Hz, 1H), 6.99- 6.78 (m, 2H), 6.70 (s, 2H),5.86 (s, 1H), 5.29-5.05 (m, 1H), 4.52- 4.29 (m, 2H), 4.22-3.98 (m, 5H),3.91 (s, 6H), 3.74 (s, 4H), 3.21- 2.72 (m, 6H), 2.66-2.40 (m, 1H), 2.35(s, 3H), 2.27-2.15 (m, 4H), 2.15-1.94 (m, 4H). D438 595.3 ¹H NMR (400MHz, DMSO-d6 with a drop of D₂O) δ 8.15 (s, 1H, FA), 8.05 (d, J = 2.7Hz, 1H), 7.82 (dd, J = 2.7, 1.3 Hz, 1H), 7.70- 7.59 (m, 3H), 6.82 (s,2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (dd, 2H), 3.86 (s, 6H), 3.66(s, 2H), 3.65-3.56 (m, 2H), 3.53 (s, 3H), 3.34 (s, 1H), 3.28 (d, J = 7.7Hz, 2H), 2.97-2.84 (m, 1H), 2.66- 2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.10(s, 3H), 2.07-1.95 (m, 1H). D439 631.3 ¹H NMR (300 MHz, Methanol-d4) δ8.25 (s, 1H), 8.11 (s, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.67 (dd, J = 7.9,1.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.09-6.61 (m, 3H), 5.17 (dd, J =13.3, 5.2 Hz, 1H), 4.61- 4.42 (m, 2H), 4.23 (s, 2H), 4.16 (t, J = 8.8Hz, 2H), 4.00 (s, 6H), 3.97- 3.85 (m, 2H), 3.77-3.63 (m, 4H), 3.03-2.75(m, 2H), 2.61-2.40 (m, 1H), 2.29-2.13 (m, 1H). D440 595.3 ¹H NMR (400MHz, Methanol-d4) δ 7.99-7.90 (m, 1H), 7.84-7.74 (m, 2H), 7.72-7.49 (m,2H), 6.91 (d, J = 2.6 Hz, 2H), 5.20-5.11 (m, 1H), 4.55-4.37 (m, 6H),4.34-4.22 (m, 2H), 4.00 (s, 6H), 3.95- 3.84 (m, 1H), 3.66 (d, J = 6.7Hz, 3H), 2.98-2.85 (m, 1H), 2.81 (s, 1H), 2.54-2.40 (m, 1H), 2.20 (d, J= 5.0 Hz, 4H). D441 631.5 ¹H NMR (400 MHz, Methanol-d4) δ 8.32-8.07 (m,2H), 7.77 (d, J = 7.8 Hz, 1H), 7.70-7.53 (m, 2H), 7.07-6.67 (m, 3H),5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.62-4.39 (m, 6H), 4.35-4.23 (m, 2H),4.17- 3.83 (m, 7H), 3.68 (s, 3H), 2.98-2.84 (m, 1H), 2.78 (d, J = 17.4Hz, 1H), 2.48 (qd, J = 13.1, 4.7 Hz, 1H), 2.22-2.14 (m, 1H). D442 609.5¹H NMR (300 MHz, Methanol-d4) δ 8.56 (s, FA, 1H), 7.96 (d, 1H),7.85-7.79 (m, 2H), 7.71-7.63 (m, 1H), 7.58 (d, 1H), 6.90 (s, 2H),5.23-5.11 (m, 1H), 4.52 (d, 2H), 4.41 (s, 2H), 4.00 (s, 6H), 3.69 (s,3H), 3.63-3.50 (m, 2H), 3.48-3.36 (m, 3H), 3.00-2.73 (m, 2H), 2.61-2.39(m, 2H), 2.31-2.11 (m, 5H). D443 623.35 ¹H NMR (300 MHz, DMSO-d6) δ11.01 (s, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.89-7.75 (m, 1H), 7.69-7.54(m, 3H), 6.82 (s, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.61-4.25 (m,2H), 3.86 (s, 6H), 3.58 (s, 2H), 3.54 (s, 3H), 3.02-2.84 (m, 1H),2.84-2.70 (m, 2H), 2.67-2.53 (m, 2H), 2.48-2.35 (m, 1H), 2.33-2.21 (m,2H), 2.10 (s, 3H), 2.06- 1.95 (m, 1H), 1.92-1.79 (m, 2H), 1.69-1.53 (m,2H). D444 659.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.40 (.1.0FA, d, J = 2.6 Hz, 1H), 8.26-8.05 (m, 2H), 7.75-7.51 (m, 3H), 7.20-6.69(m, 3H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.61-4.21 (m, 2H), 3.87 (s,6H), 3.60 (s, 3H), 3.56 (s, 2H), 3.00-2.83 (m, 1H), 2.82-2.69 (m, 2H),2.68-2.53 (m, 2H), 2.48-2.32 (m, 1H), 2.32-2.18 (m, 2H), 2.08-1.93 (m,1H), 1.84 (d, 2H), 1.70-1.49 (m, 2H). D445 707.4 ¹H NMR (300 MHz,DMSO-d6) δ 11.58 (s, 1H), 11.08 (s, 1H), 8.28- 8.13 (m, 1H, FA), 7.64(d, J = 8.3 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H),6.64 (dd, J = 8.4, 2.2 Hz, 1H), 6.51 (s, 2H), 5.06 (dd, J = 12.7, 5.2Hz, 1H), 3.74 (d, J = 8.4 Hz, 10H), 3.58 (d, J = 3.6 Hz, 5H), 2.94-2.83(m, 1H), 2.65-2.55 (m, 3H), 2.47-2.38 (m, 3H), 2.17 (s, 3H), 2.07-1.97(m, 1H), 1.79-1.67 (m, 4H), 1.51 (s, 3H). D446 707.4 ¹H NMR (300 MHz,DMSO-d6) δ 11.08 (s, 1H), 10.85 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.79(d, J = 2.1 Hz, 1H), 6.70-6.62 (m, 1H), 6.59 (s, 2H), 5.83 (s, 1H), 5.06(dd, J = 12.7, 5.3 Hz, 1H), 4.00 (s, 3H), 3.89-3.72 (m, 10H), 3.68 (s,2H), 3.00-2.78 (m, 1H), 2.70- 2.53 (m, 6H), 2.27 (s, 3H), 2.14 (s, 3H),2.09-1.96 (m, 1H), 1.81 (s, 4H). D447 666.4 ¹H NMR (300 MHz,Methanol-d4) δ 8.52 (br s, 0.2H, FA), 7.84 (d, J = 1.2 Hz, 1H), 7.64 (s,1H), 7.48 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 7.10 (s, 2H), 6.95 (d, J =2.2 Hz, 1H), 6.87 (dd, J = 8.2, 2.2 Hz, 1H), 5.20 (dd, 1H), 4.47 (d, J =5.4 Hz, 2H), 4.41 (s, 2H), 4.07 (s, 6H), 3.86-3.71 (m, 8H), 3.38-3.28(m, 3H) 3.18-2.80 (m, 2H), 2.62- 2.54 (m, 1H), 2.36-2.10 (m, 5H). D448599.35 ¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.19 (s, 1H, FA), 8.06(d, J = 2.6 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J= 7.8 Hz, 1H), 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 6.81 (s, 2H), 5.10 (dd, J= 13.3, 5.2 Hz, 1H), 4.46-4.23 (m, 2H), 3.84 (s, 6H), 3.72 (d, J = 4.9Hz, 2H), 3.53 (s, 3H), 3.46 (s, 2H), 3.07 (s, 2H), 2.96-2.85 (m, 1H),2.64-2.56 (m, 4H), 2.39 (dd, J = 13.3, 4.7 Hz, 1H), 2.10 (s, 3H),2.03-1.96 (m, 1H), 1.79 (q, J = 7.5 Hz, 2H). D449 585.35 ¹H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 8.19 (s, 1H, FA), 8.06 (d, J = 2.6 Hz,1H), 7.81 (d, J = 2.3 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H),7.44 (dd, J = 7.8, 1.6 Hz, 1H), 6.81 (s, 2H), 5.10 (dd, J = 13.3, 5.2Hz, 1H), 4.46-4.23 (m, 2H), 3.84 (s, 6H), 3.72 (d, J = 4.9 Hz, 2H), 3.53(s, 3H), 3.46 (s, 2H), 3.07 (s, 2H), 2.96-2.85 (m, 1H), 2.64-2.56 (m,4H), 2.39 (dd, J = 13.3, 4.7 Hz, 1H), 2.10 (s, 3H), 2.03-1.96 (m, 1H),1.79 (q, J = 7.5 Hz, 2H). D450 609.30 ¹H NMR (400 MHz, DMSO-d6) δ 8.22(s, 1H, FA), 8.04 (d, J = 2.7 Hz, 1H), 7.86-7.80 (m, 1H), 7.70-7.57 (m,3H), 6.82 (s, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.55-4.31 (m, 2H),3.86 (s, 6H), 3.66 (s, 2H), 3.54 (s, 3H), 3.43 (d, J = 6.8 Hz, 2H), 3.27(d, J = 6.8 Hz, 2H), 2.99-2.81 (m, 1H), 2.74-2.58 (m, 1H), 2.46-2.32 (m,1H), 2.10 (s, 3H), 2.07-1.97 (m, 1H), 1.51 (s, 3H). D451 538.25 ¹H NMR(300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.22 (s,1H), 7.61 (d, J = 7.9 Hz, 1H), 7.54-7.45 (m, 2H), 7.18- 6.74 (m, 3H),5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.43 (dd, 2H), 3.79 (s, 6H), 3.62 (s,3H), 3.04-2.91 (m, 1H), 2.67-2.59 (m, 1H), 2.47- 2.34 (m, 1H), 2.07-1.97(m, 1H). D452 600.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.39 (s,1H), 8.16 (d, J = 2.7 Hz, 1H, FA), 7.88 (dd, J = 2.7, 1.3 Hz, 1H), 7.49(d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 (d, J = 2.3Hz, 1H), 6.96 (s, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J =16.9 Hz, 1H), 4.31 (d, J = 4.2 Hz, 2H), 4.23 (d, J = 16.9 Hz, 1H), 3.96(s, 6H), 3.88 (d, J = 13.1 Hz, 2H), 3.55 (s, 3H), 3.47 (d, J = 12.0 Hz,2H), 3.33- 3.20 (m, 2H), 3.12 (t, J = 12.4 Hz, 2H), 2.98-2.84 (m, 1H),2.60 (d, J = 17.7 Hz, 1H), 2.43-2.32 (m, 1H), 2.11 (s, 3H), 2.04-1.94(m, 1H). D453 609.50 ¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.25 (s,1H, FA salt), 8.05 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H),7.63-7.56 (m, 3H), 6.82 (s, 2H), 5.10 (dd, J = 13.3, 5.2 Hz, 1H), 4.37(dd, 2H), 3.86 (s, 6H), 3.62-3.58 (m, 2H), 3.53 (s, 3H), 3.15-3.13 (m,1H), 2.96- 2.89 (m, 2H), 2.86-2.83 (m, 2H), 2.62-2.58 (m, 1H), 2.41-2.35(m, 1H), 2.09 (s, 3H), 2.03-1.98 (m, 1H), 1.11 (d, J = 5.9 Hz, 3H). D454706.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.28 (s, 1H), 7.82 (s,1H), 7.30 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.85 (s, 2H), 6.62 (d, J =8.2 Hz, 2H), 5.73-5.62 (m, 1H), 5.59-5.48 (m, 1H), 5.00 (dd, J = 13.2,5.1 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H), 4.28-4.07 (m, 2H), 3.79 (s, 6H),3.61-3.49 (m, 8H), 2.91-2.77 (m, 1H), 2.54 (d, J = 3.7 Hz, 3H),2.37-2.23 (m, 1H), 1.96-1.86 (m, 1H), 1.68 (t, J = 6.6 Hz, 4H), 1.60 (d,J = 6.3 Hz, 3H). D455 593.25 ¹H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J= 2.6 Hz, 1H), 8.11- 8.05 (m, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.99-6.78(m, 3H), 6.76 (s, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.45-4.31 (m,5H), 3.99 (q, J = 5.5, 4.1 Hz, 2H), 3.82 (s, 6H), 3.67 (s, 3H),2.97-2.83 (m, 1H), 2.83- 2.72 (m, 1H), 2.56-2.40 (m, 1H), 2.21-2.11 (m,1H). D456 666.5 ¹H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 0.67H, FA),7.93 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H),7.22-7.15 (m, 3H), 6.86 (d, J = 2.2 Hz, 1H), 6.81-6.74 (m, 1H),5.16-5.07 (m, 1H), 4.45-4.30 (m, 4H), 3.97 (s, 6H), 3.75 (s, 4H), 3.63(s, 3H), 3.39- 3.36 (m, 2H), 3.28-3.21 (m, 2H), 2.96-2.83 (m, 1H),2.82-2.72 (m, 1H), 2.56-2.40 (m, 1H), 2.19-2.02 (m, 5H). D457 597.35 ¹HNMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.67-9.52 (m, 1H, TFA salt),8.17-8.10 (m, 1H), 7.88-7.78 (m, 2H), 7.71-7.64 (m, 1H), 7.62-7.56 (m,1H), 6.98-6.91 (m, 2H), 6.71-6.62 (m, 5.7 Hz, 2H), 5.17-5.06 (m, 1H),4.49-4.41 (m, 1H), 4.41-4.27 (m, 3H), 4.27-4.22 (m, 2H), 4.16-4.15 (m,2H), 3.95 (s, 6H), 3.54 (s, 3H), 2.97-2.85 (m, 1H), 2.61 (d, J = 17.1Hz, 1H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), 2.04-1.97 (m, 2H). D458 613.35¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.89 (s, 1H), 7.79 (d, J = 8.0Hz, 2H), 7.71 (d, J = 7.9 Hz, 1H), 6.92 (s, 2H), 5.09 (dd, J = 13.3, 5.1Hz, 1H), 4.86-4.57 (m, 4H), 4.57-4.45 (m, 3H), 4.40 (d, J = 18.1 Hz,1H), 3.94 (s, 6H), 3.54 (s, 3H), 2.97-2.83 (m, 1H), 2.71-2.59 (m, 1H),2.47-2.33 (m, 1H), 2.16-2.01 (s, 4H). D459 526.2 ¹H NMR (400 MHz,DMSO-d6) δ 10.97 (s, 1H), 7.87 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 2.7,1.3 Hz, 1H), 7.46 (t, J = 8.7 Hz, 3H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H),7.25 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 5.11 (dd, J = 13.3,5.1 Hz, 1H), 4.46-4.19 (m, 2H), 3.50 (s, 3H), 3.35 (s, 8H), 2.98-2.85(m, 1H), 2.60 (d, J = 17.0 Hz, 1H), 2.43-2.32 (m, 1H), 2.07 (s, 3H),2.04-1.95 (m, 1H). D460 540.25 ¹H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J =2.7 Hz, 1H), 7.75 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 7.7 Hz, 2H), 7.43(dd, J = 11.4, 7.8 Hz, 3H), 7.27 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (s,1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.44-4.17 (m, 2H), 3.66 (s, 3H),3.52 (s, 3H), 3.24 (s, 3H), 2.97-2.84 (m, 1H), 2.77-2.64 (m, 1H), 2.67(s, 4H), 2.45- 2.33 (m, 1H), 2.09 (s, 3H), 2.04-1.95 (m, 1H). D461641.25 ¹H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.00 (s, 1H, TFA),8.49 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.32 (s, 2H), 6.77 (dt, J = 4.0,2.0 Hz, 2H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.46-4.21 (m, 4H), 4.02(s, 6H), 3.81 (s, 2H), 3.71 (s, 2H), 3.62 (s, 3H), 3.43 (d, J = 12.6 Hz,2H), 3.18 (t, J = 11.4 Hz, 2H), 3.07-2.89 (m, 1H), 2.67 (d, J = 17.2 Hz,1H), 2.56-2.31 (m, 4H), 2.19 (d, J = 14.0 Hz, 2H), 2.12- 1.98 (m, 3H),0.08 (s, 1H). D462 696.5 ¹H NMR (400 MHz, DMSO-d6 with a drop of D2O) δ8.75 (s, 1H), 8.26 (s, 1H, FA), 7.89 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H),7.24 (s, 2H), 6.74-6.67 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H),4.37-4.15 (m, 5H), 3.88 (s, 6H), 3.80 (s, 2H), 3.61 (s, 4H), 3.55 (s,3H), 2.95-2.82 (m, 1H), 2.81-2.57 (m, 5H), 2.45-2.31 (m, 1H), 2.06-1.95(m, 1H), 1.85 (t, J = 5.5 Hz, 4H). D463 654.35 ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (s, 1H), 8.28 (d, J = 1.1 Hz, 1H), 7.87 (d, J = 1.7Hz, 1H), 7.73 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.48(d, J = 8.5 Hz, 1H), 7.39-7.31 (m, 2H), 7.15 (s, 1H), 5.95-5.80 (m, 1H),5.71-5.54 (m, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 (d, J = 6.4 Hz,2H), 4.48-4.34 (m, 2H), 4.01 (t, J = 5.3 Hz, 2H), 3.59-3.52 (m, 2H),3.42-3.38 (m, 2H), 3.36-3.32 (m, 1H), 3.28-3.20 (m, 1H), 2.95-2.83 (m,1H), 2.82-2.73 (m, 1H), 2.56-2.42 (m, 1H), 2.23-2.13 (m, 1H), 1.73 (dd,J = 6.5, 1.6 Hz, 3H). D464 704.1 ¹H NMR (300 MHz, DMSO-d6) δ 11.04 (s,1H), 8.22 (s, 1H), 8.08- 7.95 (m, 3H), 7.92 (s, 1H), 7.79 (s, 1H), 7.67(s, 2H), 7.05 (s, 1H), 5.82-5.66 (m, 1H), 5.66-5.51 (m, 1H), 5.18 (dd, J= 13.2, 5.1 Hz, 1H), 4.68-4.46 (m, 3H), 4.41 (d, J = 6.0 Hz, 2H), 3.51(s, 2H), 3.02- 2.84 (m, 8H), 2.62 (d, J = 17.0 Hz, 1H), 2.49-2.34 (m,1H), 2.05 (dd, J = 12.7, 6.4 Hz, 1H), 1.65 (dd, J = 6.3, 1.4 Hz, 3H).D465 680.4 ¹H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.86 (s, 1H),7.68- 7.60 (m, 2H), 7.52 (dd, J = 7.9, 1.8 Hz, 1H), 7.27 (d, J = 8.2 Hz,1H), 6.79-6.73 (m, 2H), 6.67 (dd, J = 8.2, 2.3 Hz, 1H), 5.82-5.68 (m,1H), 5.61-5.47 (m, 1H), 5.02 (dd, J = 13.3, 5.2 Hz, 1H), 4.39 (d, J =6.3 Hz, 2H), 4.34-4.20 (m, 2H), 3.71 (s, 2H), 3.59 (s, 4H), 2.87- 2.74(m, 1H), 2.72-2.65 (m, 1H), 2.62-2.51 (m, 4H), 2.45-2.31 (m, 1H),2.10-2.03 (m, 1H), 1.87-1.81 (m, 4H), 1.63 (dd, J = 6.5, 1.5 Hz, 3H).D466 640.4 ¹H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.32 (s, 1H),8.02- 7.76 (m, 4H), 7.61-7.49 (m, 1H), 7.43-7.27 (m, 2H), 7.16 (s, 1H),5.90-5.76 (m, 1H), 5.74-5.60 (m, 1H), 5.18 (dd, J = 13.2, 5.1 Hz, 1H),4.88-4.57 (m, 1H), 4.54-4.38 (m, 3H), 4.36-4.24 (m, 1H), 4.10-3.56 (m,3H), 3.32-3.14 (m, 3H), 3.07-2.90 (m, 2H), 2.75- 2.62 (m, 3H), 2.52-2.38(m, 1H), 2.14-2.04 (m, 1H), 1.78-1.70 (m, 3H). D467 719.45 ¹H NMR (400MHz, DMSO-d6) δ 11.18 (d, J = 6.1 Hz, 1H), 10.96 (s, 1H), 8.94 (s, 1H,TFA), 7.40 (d, J = 8.9 Hz, 1H), 7.11 (s, 1H), 6.89 (s, 2H), 6.70 (h, J =2.3 Hz, 2H), 6.35 (s, 1H), 5.67-5.55 (m, 1H), 5.45-5.29 (m, 1H), 5.15(d, J = 5.5 Hz, 2H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.32 (d, J = 16.7Hz, 1H), 4.25 (d, J = 4.6 Hz, 2H), 4.19 (d, J = 16.6 Hz, 1H), 3.93 (s,6H), 3.75 (s, 2H), 3.64 (s, 2H), 3.41-3.33 (m, 2H), 3.11 (q, J = 11.1Hz, 2H), 2.90 (ddd, J = 17.5, 13.4, 5.4 Hz, 1H), 2.70-2.52 (m, 1H), 2.39(dd, J = 13.2, 8.5 Hz, 1H), 2.34 (s, 3H), 2.12 (d, J = 13.9 Hz, 2H),2.04-1.94 (m, 3H), 1.62 (dd, J = 6.6, 1.6 Hz, 3H). D468 679.5 ¹H NMR(400 MHz, DMSO-d6) δ 11.19 (d, J = 6.2 Hz, 1H), 10.98 (s, 1H), 9.42 (s,1H, TFA), 7.50 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H),7.29-7.20 (m, 1H), 7.12 (d, J = 6.0 Hz, 1H), 6.90 (s, 2H), 6.36 (s, 1H),5.66-5.54 (m, 1H), 5.45-5.29 (m, 1H), 5.15 (d, J = 5.6 Hz, 1H), 5.10(dd, J = 13.3, 5.1 Hz, 1H), 4.36 (d, J = 16.8 Hz, 3H), 4.23 (d, J = 16.9Hz, 1H), 3.94 (s, 6H), 3.89 (d, J = 12.9 Hz, 2H), 3.74 (d, J = 7.0 Hz,1H), 3.54-3.46 (m, 2H), 3.29 (d, J = 11.7 Hz, 2H), 3.14 (t, J = 12.1 Hz,2H), 2.91 (ddd, J = 17.6, 13.6, 5.4 Hz, 1H), 2.60 (d, J = 17.0 Hz, 1H),2.46-2.33 (m, 1H), 2.34 (s, 3H), 2.03-1.95 (m, 1H), 1.81-1.59 (m, 3H).D469 654.25 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.35 (s, 1H),7.88 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.29-7.20 (m, 1H), 7.20-7.06 (m,2H), 6.92 (s, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.37-4.15 (m, 2H),3.86 (s, 6H), 3.66-3.51 (m, 2H), 3.43 (s, 3H), 3.11-2.85 (m, 5H),2.70-2.55 (m, 3H), 2.43-2.31 (m, 1H), 2.05-1.93 (m, 1H), 1.39-1.14 (m,6H). D470 666.735 D471 666.45 ¹H NMR (300 MHz, Methanol-d4) δ 9.62 (s,1H), 8.72 (d, J = 6.3 Hz, 1H), 8.15 (d, J = 7.0 Hz, 1H), 8.05 (s, 1H),7.93 (d, J = 6.3 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 6.90 (s, 2H), 6.79(dd, J = 7.1, 2.4 Hz, 1H), 4.96 (d, J = 9.1 Hz, 1H), 4.47 (s, 2H), 4.27(s, 2H), 4.15 (s, 2H), 3.99 (s, 6H), 3.76 (s, 3H), 3.63 (d, J = 13.1 Hz,2H), 3.25 (t, J = 12.2 Hz, 2H), 2.94-2.70 (m, 2H), 2.27 (dt, J = 28.7,13.5 Hz, 6H). D472 667.20 ¹H NMR (300 MHz, Methanol-d4) δ 9.55 (d, J =0.8 Hz, 1H), 8.70 (d, J = 5.8 Hz, 1H), 8.56 (d, J = 5.0 Hz, 1H), 7.77(s, 1H), 7.64 (d, J = 5.8, 0.9 Hz, 1H), 7.28 (d, J = 4.9 Hz, 1H), 6.85(s, 2H), 4.82 (dd, J = 12.6, 5.4 Hz, 1H), 4.20 (s, 2H), 4.06-3.91 (m,10H), 3.72 (s, 3H), 3.06 (d, J = 27.6 Hz, 4H), 2.95-2.65 (m, 2H),2.43-2.27 (m, 1H), 2.20 (s, 1H), 2.14-1.99 (m, 4H). D473 667.20 ¹H NMR(400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.48 (s, 1H), 9.02 (d, J = 15.8 Hz,1H), 8.73 (dd, J = 16.7, 7.0 Hz, 2H), 8.40 (s, 1H), 8.10 (s, 1H), 7.91(s, 1H), 7.60 (d, J = 5.7 Hz, 1H), 6.88 (s, 2H), 4.84- 4.73 (m, 1H),4.30 (d, J = 4.6 Hz, 2H), 4.02 (s, 2H), 3.91 (s, 8H), 3.62 (s, 3H), 3.40(d, J = 12.2 Hz, 2H), 3.21-3.02 (m, 2H), 2.82 (s, 1H), 2.55 (d, J = 3.7Hz, 1H), 2.25-2.11 (m, 3H), 2.08-1.91 (m, 3H). D474 677.45 ¹H NMR (300MHz, DMSO-d6) δ 10.98 (s, 1H), 9.45 (s, 1H), 8.74 (d, J = 5.7 Hz, 1H),7.89 (s, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 6.76(s, 2H), 6.70-6.61 (m, 2H), 4.80-4.67 (m, 1H), 4.33 (s, 2H), 3.83 (s,6H), 3.67-3.53 (m, 9H), 3.03-2.88 (m, 2H), 2.78-2.64 (m, 2H), 2.60-2.53(m, 4H), 1.82-1.69 (m, 4H). D475 748.35 ¹H NMR (400 MHz, Methanol-d4) δ7.42 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.03 (d, J = 3.2 Hz, 1H),6.90-6.85 (m, 3H), 6.82-6.78 (m, 2H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H),4.64-4.49 (m, 2H), 4.45-4.34 (m, 4H), 4.25-4.13 (m, 2H), 3.97 (s, 6H),3.87-3.71 (m, 4H), 3.66 (s, 3H), 3.62-3.46 (m, 5H), 3.44-3.38 (m, 4H),3.16-3.05 (m, 1H), 2.98-2.86 (m, 1H), 2.85-2.75 (m, 1H), 2.56-2.42 (m,1H), 2.32-2.06 (m, 5H). D476 693.2 ¹H NMR (400 MHz, DMSO-d6) δ 11.90 (s,1H), 11.08 (s, 1H), 8.25 (s, 1H, FA), 7.63 (d, J = 8.3 Hz, 1H), 7.43 (s,1H), 6.84-6.75 (m, 3H), 6.65 (dd, J = 8.5, 2.2 Hz, 1H), 6.29 (s, 1H),5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.84 (s, 6H), 3.73 (s, 4H), 3.58 (s,3H), 3.52 (s, 2H), 2.94-2.85 (m, 1H), 2.62-2.55 (m, 2H), 2.44-2.37 (m,3H), 2.37- 2.31 (m, 4H), 2.06-1.96 (m, 1H), 1.73 (t, J = 5.2 Hz, 4H).

Example 85—Preparation of Compounds DD11-DD16

In analogy to the procedures described in the examples above, compoundsDD11-DD16 were prepared using the appropriate starting materials.

Compound No. LCMS ¹H NMR DD11 785.35 ¹H NMR (300 MHz, DMSO) δ 11.13 (s,1H), 8.20 (s, FA, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.88-7.80 (m, 2H), 7.74(s, 1H), 7.56-7.48 (m, 1H), 7.47-7.39 (m, 1H), 7.39-7.35 (m, 1H),7.34-7.23 (m, 2H), 6.73 (s, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H),5.06-4.91 (m, 1H), 3.81 (s, 6H), 3.70 (s, 2H), 3.58-3.50 (m, 1H),3.00-2.81 (m, 4H), 2.66-2.53 (m, 1H), 2.49-2.38 (m, 4H), 2.35-2.18 (m,6H), 2.14- 1.99 (m, 3H), 1.86-1.75 (m, 2H), 1.72-1.61 (m, 4H), 1.60-1.49(m, 3H), 1.27-1.07 (m, 2H). DD12 519.45 ¹H NMR (400 MHz, DMSO-d6) δ10.97 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.3 Hz, 1H),6.72-6.64 (m, 4H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.35-4.12 (m, 2H),3.79 (s, 6H), 3.64 (s, 2H), 3.57 (s, 4H), 2.98-2.84 (m, 1H), 2.64-2.55(m, 5H), 2.45-2.33 (m, 1H), 2.02-1.94 (m, 1H), 1.79-1.72 (m, 4H). DD13676.35 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.30 (dd, J = 8.2, 1.4Hz, 1H), 7.71 (dd, J = 7.4, 1.4 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.45(d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 4.3 Hz, 4H),6.56 (d, J = 7.6 Hz, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.36-4.13 (m,2H), 3.82 (s, 7H), 3.60 (d, J = 4.4 Hz, 7H), 3.53 (s, 3H), 2.98- 2.84(m, 1H), 2.64-2.55 (m, 2H), 2.38 (dd, J = 13.2, 4.6 Hz, 2H), 2.03-1.94(m, 1H), 1.75 (t, J = 5.4 Hz, 4H). DD14 479.30 ¹H NMR (300 MHz,Methanol-d4) δ 8.52 (s, 0.48H, FA), 7.53-7.40 (m, 2H), 7.40-7.32 (m,2H), 6.78 (d, J = 8.4 Hz, 2H) 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.52-4.35(m, 2H), 4.27 (s, 2H), 3.93 (s, 6H), 3.62-3.39 (m, 4H), 3.30-3.18 (m,4H), 3.12-2.73 (m, 2H), 2.62- 2.41 (m, 1H), 2.26-2.12 (m, 1H). DD15652.30 ¹H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.97 (s, 1H), 8.22-8.13 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 6.74-6.34 (m, 4H), 5.07 (dd, J =13.6, 5.2 Hz, 1H), 4.34-4.14 (m, 2H), 3.88 (s, 6H), 3.65-3.57 (m, 6H),2.94-2.86 (m, 1H), 2.67-2.59 (m, 1H), 2.47-2.26 (m, 5H), 2.04-1.93 (m,1H), 1.84-1.59 (m, 4H). DD16 518.15 ¹H NMR (300 MHz, DMSO-d6) δ 10.98(s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.66-7.53(m, 1H), 7.45 (m, J = 8.4 Hz, 1H), 7.37-7.08 (m, 2H), 6.74 (m, J = 7.5,0.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44-4.13 (m, 2H), 4.00(s, 1H), 3.89-3.67 (m, 2H), 3.52 (s, 3H), 3.00-2.91 (m, 3H), 2.63 (m,1H), 2.45-2.23 (m, 1H), 2.11-1.94 (m, 1H), 1.95-1.81 (m, 2H), 1.71-1.61(m, 2H).

Example 86—BRD9 Bromodomain TR-FRET Competition Binding Assay

This example demonstrates the ability of the compounds of the disclosureto biochemically inhibit BRD9 bromodomain in a competition bindingassay.

Procedure:

His-Flag-BRD9 (P133-K239; Swiss Prot Q9H8M2; SEQ ID NO:1mgsshhhhhhenlyfq/gdykddddkgslevlfqg/PAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMIIKHPMDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSK) wascloned, expressed, purified, and then treated with TEV protease. CleavedHis tag was removed by purification. The binding of a biotinylated smallmolecule ligand of BRD9 was assessed via the LANCE® TR-FRET platform(PerkinElmer), and the compounds were assayed for inhibitory activityagainst this interaction.

A mixture of biotinylated-ligand and SureLight™Allophycocyanin-Streptavidin (APC-SA, PerkinElmer AD0201) in 50 mM HEPES(pH 7.4), 50 mM NaCl, 1 mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01%(w/v) bovine serum albumin was added to a white 384-well PerkinElmerProxiplate Plus plate. DMSO or 3-fold serially diluted compounds werethen added to the Proxiplate followed by addition of Flag-BRD9. After a10-minute incubation at room temperature, Eu-W1024 anti-FLAG(PerkinElmer, AD0273) was added. The final reaction mixture thatcontained 3.75 nM biotinylated ligand, 3 nM Flag-BRD9, 7.5 nM SureLight™Allophycocyanin-Streptavidin, and 0.2 nM Eu-W1024 anti-FLAG wasincubated at room temperature for 90 minutes.

Results:

The plates were then read on a PerkinElmer Envision plate reader todetermine the ratio of emission at 665 nm over 615 nm. Data wasnormalized to a DMSO control (100%) and a no protein control (0%) andthen fit to a four parameter, non-linear curve fit to calculate IC₅₀(μM) values as shown in Table 4. As shown by the results in Table 4, anumber of compounds of the present disclosure exhibit an IC₅₀ value of<1 μM for BRD9 binding, indicating their affinity for targeting BRD9.

TABLE 4 Bromodomain 9 (BRD9) TR-FRET Binding of Compounds of theDisclosure Compound No. Bromodomain TR-FRET BRD9 IC₅₀ (nM) D1 +++ D2++++ D3 ++++ D4 ++++ D5 ++++ D6 ++++ D7 ++++ D8 ++++ D9 ++++ D10 +++ D11+++ D12 ++++ D13 ++++ D14 ++++ D15 ++++ D16 NT D17 NT D18 NT D19 NT D20NT D21 NT D22 ++++ D23 ++++ D24 NT D25 ++++ D26 +++ D27 ++++ D28 NT D29NT D30 ++++ D31 ++++ D32 ++++ D33 ++++ D34 ++++ D35 ++++ D36 ++++ D37++++ D38 ++++ D39 ++++ D40 ++++ D41 ++++ D42 NT D43 NT D44 NT D45 NT D46NT D47 NT D48 NT D49 NT D50 NT D51 NT D52 ++++ D53 ++++ D54 +++ D55 +++D56 ++++ D57 +++ D58 ++++ D59 ++++ D60 ++++ D61 ++++ D62 +++ D63 +++ D64+++ D65 +++ D66 +++ D67 ++++ D68 ++++ D69 ++++ D70 +++ D71 ++++ D72 ++++D73 +++ D74 ++++ D75 NT D76 NT D77 NT D78 NT D79 NT D80 NT D81 NT D82 NTD83 NT D84 +++ D85 +++ D86 +++ D87 ++++ D88 ++++ D89 ++++ D90 ++++ D91+++ D92 ++++ D93 ++++ D94 +++ D95 +++ D96 ++++ D97 ++++ D98 ++ D99 +++D100 ++++ D101 ++++ D102 ++++ D103 +++ D104 +++ D105 +++ D106 +++ D107+++ D108 ++++ D109 ++++ D110 +++ D111 ++++ D112 ++++ D113 ++++ D114 ++++D115 +++ D116 ++++ D117 ++++ D118 ++++ D119 ++++ D120 +++ D121 +++ D122++++ D123 ++++ D124 ++++ D125 ++++ D126 +++ D127 ++++ D128 +++ D129 ++++D130 ++++ D131 ++++ D132 ++++ D133 ++++ D134 +++ D135 +++ D136 ++++ D137++++ D138 ++++ D139 ++++ D140 ++++ D141 +++ D142 +++ D143 ++++ D144 +++D145 +++ D146 ++++ D147 +++ D148 +++ D149 ++++ D150 ++++ D151 ++++ D152++++ D153 +++ D154 ++++ D155 ++++ D156 ++++ D157 +++ D158 ++++ D159 ++++D160 ++++ D161 ++++ D162 +++ D163 ++++ D164 ++++ D165 +++ D166 ++++ D167++++ D168 ++++ D169 ++++ D170 +++ D171 +++ D172 ++++ D173 +++ D174 +++D175 +++ D176 ++++ D177 ++++ “+” indicates inhibitory effect of ≥1000nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicatesinhibitory effect of ≥10 nM; “++++” indicates inhibitory effect of <10nM; “NT” indicates not tested

Example 87—SYO1 BRD9 NanoLuc Degradation Assay

This example demonstrates the ability of the compounds of the disclosureto degrade a Nanoluciferase-BRD9 fusion protein in a cell-baseddegradation assay.

Procedure:

A stable SYO-1 cell line expressing 3×FLAG-NLuc-BRD9 was generated. Onday 0 cells were seeded in 30 μL media into each well of 384-well cellculture plates. The seeding density was 8000 cells/well. On day 1, cellswere treated with 30 nL DMSO or 30 nL of 3-fold serially DMSO-dilutedcompounds (10 points in duplicates with 1 μM as final top dose).Subsequently plates were incubated for 6 hours in a standard tissueculture incubator and equilibrated at room temperature for 15 minutes.Nanoluciferase activity was measured by adding 15 μL of freshly preparedNano-Glo Luciferase Assay Reagent (Promega N1130), shaking the platesfor 10 minutes and reading the bioluminescence using an EnVision reader.

Results:

The Inhibition % was calculated using the following formula: %Inhibition=100×(Lum_(HC)−Lum_(Sample))/(Lum_(HC)−Lum_(LC)). DMSO treatedcells are employed as High Control (HC) and 1 μM of a known BRD9degrader standard treated cells are employed as Low Control (LC). Thedata was fit to a four parameter, non-linear curve fit to calculate IC₅₀(μM) values as shown in Table 5A, Table 5B, and Table 5C. As shown bythe results in Table 5A, Table 5B3, and Table 50, a number of compoundsof the present disclosure exhibit an IC₅₀ value of <1 μM for thedegradation of BRD9, indicating their use as compounds for reducing thelevels and/or activity of BRD9 and their potential for treatingBRD9-related disorders.

TABLE 5A SYO1 Bromodomain 9-NanoLuc Degradation by Compounds of theDisclosure Compound No. SYO1 BRD9-NanoLuc degradation IC₅₀ (nM) D1 ++++D2 +++ D3 ++++ D4 +++ D5 +++ D6 ++++ D7 +++ D8 + D9 ++++ D10 ++++ D11++++ D12 ++++ D13 ++++ D14 ++++ D15 ++++ D16 ++++ D17 ++++ D18 ++++ D19++++ D20 ++++ D21 + D22 +++ D23 ++++ D24 +++ D25 ++ D26 + D27 +++ D28 ++D29 +++ D30 +++ D31 +++ D32 +++ D33 ++++ D34 ++++ D35 ++++ D36 ++ D37++++ D38 ++++ D39 ++++ D40 ++++ D41 +++ D42 ++++ D43 ++ D44 ++++ D45++++ D46 ++++ D47 ++++ D48 +++ D49 + D50 ++++ D51 ++++ D52 ++++ D53 ++++D54 +++ D55 ++ D56 ++++ D57 ++++ D58 ++++ D59 ++++ D60 ++++ D61 +++ D62++ D63 +++ D64 ++ D65 ++ D66 ++ D67 ++++ D68 ++ D69 ++++ D70 +++ D71++++ D72 ++++ D73 ++++ D74 ++ D75 ++++ D76 ++++ D77 ++ D78 +++ D79 ++D80 ++++ D81 ++++ D82 +++ D83 ++ D84 + D85 ++ D86 ++ D87 +++ D88 +++ D89++++ D90 +++ D91 +++ D92 ++++ D93 +++ D94 +++ D95 ++ D96 +++ D97 +++ D98++ D99 +++ D100 ++++ D101 ++ D102 +++ D103 +++ D104 ++ D105 ++ D106 ++D107 +++ D108 ++++ D109 +++ D110 +++ D111 +++ D112 ++ D113 ++++ D114 +++D115 ++ D116 +++ D117 ++ D118 +++ D119 +++ D120 +++ D121 +++ D122 ++++D123 ++++ D124 ++++ D125 +++ D126 ++ D127 ++ D128 ++++ D129 ++++ D130++++ D131 ++++ D132 ++++ D133 +++ D134 +++ D135 ++ D136 ++ D137 +++ D138+++ D139 ++ D140 +++ D141 ++ D142 +++ D143 ++++ D144 +++ D145 +++ D146+++ D147 +++ D148 ++ D149 +++ D150 +++ D151 +++ D152 ++++ D153 +++ D154+++ D155 +++ D156 +++ D157 ++++ D158 +++ D159 +++ D160 +++ D161 +++ D162+++ D163 +++ D164 +++ D165 +++ D166 +++ D167 ++++ D168 ++++ D169 +++D170 ++++ D171 ++++ D172 +++ D173 ++++ D174 ++ D175 +++ D176 ++++ D177+++ “+” indicates inhibitory effect of ≥1000 nM; “++” indicatesinhibitory effect of ≥100 nM; “+++” indicates inhibitory effect of ≥10nM; “++++” indicates inhibitory effect of <10 nM; “NT” indicates nottested

TABLE 5B SYO1 Bromodomain 9-NanoLuc Degradation by Compounds of theDisclosure Compound No. SYO1 BRD9-NanoLuc degradation IC₅₀ (nM) D178++++ D179 +++ D180 ++++ D181 ++ D182 +++ D183 ++ D184 ++++ D185 ++++D186 ++++ D187 ++++ D188 ++++ D189 ++++ D190 +++ D191 ++++ D192 ++ D193++ D194 ++++ D195 +++ D196 +++ D197 ++++ D198 ++++ D199 ++++ D200 +++D201 ++++ D202 ++++ D203 ++++ D204 ++++ D205 ++++ D206 ++++ D207 ++++D208 ++++ D209 ++ D210 +++ D211 ++++ D212 +++ D213 ++++ D214 ++++ D215++++ D216 ++++ D217 ++++ D218 ++++ D219 ++++ D220 ++++ D221 ++++ D222++++ D223 ++++ D224 ++++ D225 ++++ D226 ++++ D227 ++++ D228 ++++ D229++++ D230 ++++ D231 ++ D232 +++ D233 ++ D234 +++ D235 ++++ D236 ++++D237 ++++ D238 ++++ D239 ++++ D240 ++++ D241 ++++ D242 ++++ D243 ++++D244 ++++ D245 +++ D246 ++++ D247 ++++ D248 +++ D249 +++ D250 ++++ D251++++ D252 ++++ D253 ++++ D254 ++++ D255 ++++ D256 ++++ D257 ++++ D258++++ D259 ++++ D260 ++++ D261 ++++ D262 ++++ D263 ++++ D264 +++ D265 ++D266 +++ D267 +++ D268 ++++ D269 ++++ D270 +++ D271 ++++ D272 ++++ D273++++ D274 ++++ D275 ++++ D276 +++ D277 ++++ D278 +++ D279 ++++ D280 ++++D281 +++ D282 ++ D283 ++ D284 +++ D285 ++ D286 +++ D287 ++++ D288 ++++D289 ++++ D290 ++++ D291 ++++ D292 ++ D293 +++ D294 ++ D295 ++ D296 ++D297 ++++ D298 ++++ D299 ++++ D300 ++++ D301 ++++ D302 ++++ D303 +++D304 ++++ D305 ++ D306 ++++ D307 ++++ D308 ++++ D309 +++ D310 ++++ D311+++ D312 ++++ D313 ++++ D314 +++ D315 ++++ D316 ++++ D317 +++ D318 ++++D319 ++++ D320 ++++ D321 ++++ D322 ++++ D323 ++++ D324 ++++ D325 ++++D326 ++++ D327 ++++ D328 ++++ D329 ++++ D330 ++++ D331 ++++ D332 ++++D333 ++++ D334 + D335 ++++ D336 ++++ D337 ++++ D338 ++++ D339 ++++ D340++++ D341 ++++ D342 + D343 ++++ D344 ++++ D345 ++++ D346 ++++ D347 ++++D348 ++++ D349 ++++ D350 ++ D351 + D352 + D353 ++++ D354 ++++ D355 +D356 ++++ D357 ++++ D358 ++++ D359 ++++ D360 ++++ D361 ++++ D362 ++++D363 ++++ D364 ++ D365 +++ D366 ++++ D367 ++++ D368 ++++ D369 ++++ D370++++ D371 ++++ DD1 + DD2 ++ DD3 + DD4 ++++ DD5 +++ DD6 +++ DD7 ++++ DD8++++ DD9 ++++ DD10 ++ “+” indicates inhibitory effect of ≥1000 nM; “++”indicates inhibitory effect of ≥100 nM; “+++” indicates inhibitoryeffect of ≥10 nM; “++++” indicates inhibitory effect of <10 nM; “NT”indicates not tested

TABLE 5C SYO1 Bromodomain 9-NanoLuc Degradation by Compounds of theDisclosure Compound No. SYO1 BRD9-NanoLuc degradation IC₅₀ (nM) D372++++ D373 ++++ D374 ++++ D375 ++++ D376 ++++ D377 ++++ D378 ++++ D379++++ D380 +++ D381 ++++ D382 ++++ D383 + D384 ++++ D385 ++++ D386 ++++D387 ++++ D388 ++++ D389 + D390 + D391 ++ D392 +++ D393 +++ D394 + D395++++ D396 ++++ D397 ++++ D398 ++++ D399 ++++ D400 ++++ D401 ++++ D402++++ D403 ++++ D404 ++++ D405 ++++ D406 ++++ D407 ++++ D408 ++++ D409++++ D410 ++++ D411 ++++ D412 ++++ D413 ++++ D414 ++++ D415 ++++ D416++++ D417 ++++ D418 ++++ D419 ++++ D420 ++++ D421 ++++ D422 ++++ D423++++ D424 ++++ D425 ++++ D426 ++++ D427 ++++ D428 ++++ D429 + D430 ++++D431 ++++ D432 +++ D433 ++++ D434 ++++ D435 + D436 ++++ D437 + D438 ++++D439 ++++ D440 ++++ D441 ++++ D442 ++++ D443 ++++ D444 ++++ D445 +D446 + D447 ++ D448 ++++ D449 +++ D450 ++++ D451 +++ D452 ++++ D453 ++++D454 ++++ D455 ++++ D456 ++++ D457 ++++ D458 ++++ D459 ++++ D460 ++++D461 +++ D462 ++++ D463 ++++ D464 + D465 ++++ D466 ++++ D467 + D468 +D469 NT D470 NT D471 ++++ D472 + D473 + D474 + D475 +++ D476 ++++ DD11 +DD12 + DD13 +++ DD14 + DD15 +++ DD16 +++ “+” indicates inhibitory effectof ≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++”indicates inhibitory effect of ≥10 nM; “++++” indicates inhibitoryeffect of <10 nM; “NT” indicates not tested

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificembodiments thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are in the claims.

1. (canceled)
 2. A compound of Formula I:A-L-B  I or a pharmaceutically acceptable salt thereof, wherein: A hasthe structure of Formula IIIc:

wherein: A¹ is a bond between L and A; R⁴ is —CH₃; R⁵ is H; R^(6a) is H,F, cyano,

R^(6b) is H or —CH₃; B has the structure of Formula AA0:

wherein: A² is a bond between B and L; v1 is 0, 1, 2, 3, 4, or 5; R^(A5)is H; J^(A) is absent, O, optionally substituted amino, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl; Jis absent, optionally substituted C₃-C₁₀ carbocyclylene, optionallysubstituted C₆-C₁₀ arylene, optionally substituted C₂-C₉heterocyclylene, or optionally substituted C₂-C₉ heteroarylene; L hasthe structure of Formula IIg:A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-A²  IIg wherein: each of n and o1 is,independently, 0 or 1;

E³ is

F¹ is

 and F² is

 and wherein any optionally substituted alkyl, heteroalkyl,carbocyclene, arylene, heterocyclylene, or heteroarylene is optionallysubstituted with 1-4 substituents selected from alkyl, aryl,carbocyclyl, halogen, hydroxyl, heteroalkyl, heteroaryl, heterocyclyl,amino, azido, cyano, nitro, oxo, sulfonyl, and thiol.
 3. The compound ofclaim 2, wherein v1 is
 0. 4. The compound of claim 3, wherein J^(A) isabsent.
 5. The compound of claim 3, wherein J^(A) is O or optionallysubstituted amino.
 6. The compound of claim 3, wherein J is optionallysubstituted C₂-C₉ heterocyclylene or optionally substituted C₂-C₉heteroarylene.
 7. The compound of claim 6, wherein J is optionallysubstituted C₂-C₉ heterocyclylene.
 8. The compound of claim 3, wherein Jis optionally substituted C₃-C₁₀ carbocyclylene or optionallysubstituted C₆-C₁₀ arylene.
 9. The compound of claim 8, wherein J isoptionally substituted C₆-C₁₀ arylene.
 10. The compound of claim 2,wherein B is


11. The compound of claim 2, wherein R^(6a) is H or —CH₃.
 12. Thecompound of claim 11, wherein R^(6a) is —CH₃.
 13. The compound of claim2, wherein R^(6b) is —CH₃.
 14. The compound of claim 2, wherein thecompound is selected from D328, D329, D330, D334, D343, D344, D362,D398, D399, D436, D448, D449, and D452, or a pharmaceutically acceptablesalt thereof.